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ATRXc.371-1G>ANot classified
Print report
Variant interpretation report

ATRX c.371-1G>A, p.?

NM_000489.5:c.371-1G>A NP_000480.3:p.? View identifiers
Classification
Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About ATRX

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

This variant disrupts the canonical splice acceptor site at intron 5 of ATRX (c.371-1G>A, ±1 position). ATRX loss of function is an established disease mechanism for ATR-X syndrome (alpha-thalassemia/mental retardation syndrome, X-linked, MIM #301040), supported by germline disease literature. Under the ClinGen SVI PVS1 decision tree (PMC6185798), canonical ±1,2 splice site variants in genes with a validated germline loss-of-function mechanism qualify for PVS1 at full strength. SpliceAI predicts near-complete acceptor loss (delta score 0.99), consistent with aberrant splicing and a predicted null effect.

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD-Canada v1.0. gnomAD v2.1 and v4.1 population frequency data were unavailable due to query timeout, but the clinical laboratory submission (Invitae) independently confirmed absence from population databases. As a canonical splice site variant on the X chromosome causing a well-established X-linked disorder, standing population variation is expected to be exceedingly low. The combined evidence supports rarity consistent with PM2 at moderate strength under generic ACMG/AMP 2015.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Not classified

No source classification-combination explanation was recorded.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.990 maximum delta

Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Likely pathogenic.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Statement recorded

In progress — evidence not uploaded yet.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 6 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000489.5:c.371-1G>A disrupts the canonical splice acceptor site at intron 5 of ATRX, a gene in which germline loss of function is an established mechanism for ATR-X syndrome (MIM #301040). Under the ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong strength.

The variant is absent from gnomAD-Canada v1.0 and independently reported as absent from population databases by the submitting clinical laboratory (Labcorp Genetics/Invitae). This rarity, combined with its location on the X chromosome in a gene causing an X-linked disorder, meets PM2 at moderate strength.

SpliceAI predicts complete acceptor loss (max delta 0.99, DS_AL 0.99), consistent with the predicted loss-of-function effect. Per PMC6185798, PP3 is not stacked with PVS1 for the same splice prediction evidence.

No variant-specific functional data (PS3), de novo reports (PS2/PM6), segregation data (PP1), or proband phenotype details (PP4) are available in the case materials. ClinVar classification is from a single submitter (1-star) and does not meet PP5 threshold.

Combined ACMG evidence: PVS1 (very strong) + PM2 (moderate). Under generic ACMG/AMP 2015 combination rules, one very strong and one moderate criterion yields a classification of Likely Pathogenic.

Met · 2

PVS1 Very strongThis variant disrupts the canonical splice acceptor site at intron 5 of ATRX (c.371-1G>A, ±1 position). ATRX loss of function is an established disease mechanism for ATR-X syndrome (alpha-thalassemia/mental retardation syndrome, X-linked, MIM #301040), supported by germline disease literature. Under the ClinGen SVI PVS1 decision tree (PMC6185798), canonical ±1,2 splice site variants in genes with a validated germline loss-of-function mechanism qualify for PVS1 at full strength. SpliceAI predicts near-complete acceptor loss (delta score 0.99), consistent with aberrant splicing and a predicted null effect. Details ▾Hide ▴
Evidence considered
  • Canonical splice acceptor site (±1
  • 2 position) disrupted by c.371-1G>A
  • ATRX germline loss of function is an established disease mechanism for ATR-X syndrome (PMID:29706636)
  • ClinGen SVI PVS1 decision tree (PMC6185798) supports default PVS1 for canonical splice variants in LoF-eligible genes
  • SpliceAI max delta score 0.99 with acceptor loss (DS_AL) of 0.99
  • predicting complete splicing disruption
Still missing
  • Confirm transcript NM_000489.5 is the clinically relevant isoform for the proband's phenotype
  • Verify absence of alternative in-frame transcripts that could rescue function
Sources
pvs1_generic_frameworkpvs1_gene_contextpvs1_variant_assessmentspliceai ↗
PM2 ModerateThis variant is absent from gnomAD-Canada v1.0. gnomAD v2.1 and v4.1 population frequency data were unavailable due to query timeout, but the clinical laboratory submission (Invitae) independently confirmed absence from population databases. As a canonical splice site variant on the X chromosome causing a well-established X-linked disorder, standing population variation is expected to be exceedingly low. The combined evidence supports rarity consistent with PM2 at moderate strength under generic ACMG/AMP 2015. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes)
  • Invitae clinical submission independently reports absence from gnomAD
  • Canonical splice site variant on chromosome X with established disease association
Still missing
  • Confirm absence in gnomAD v2.1 and v4.1 when data becomes available
  • Population frequency data limited by gnomAD query timeout
Sources
gnomad_canada ↗clinvar ↗

Not met · 6 · evaluated, threshold not reached

PS3 No variant-specific functional data identified for NM_000489.5:c.371-1G>A. The available literature discusses ATRX mutations at the gene level but does not report experimental functional characterization of this specific splice variant. PMID:23681356 describes brain MRI findings in 27 ATR-X patients but provides no functional assay data for c.371-1G>A. PMID:36496321 describes genetic testing results in hypospadias patients without functional characterization. No experimental evidence (luciferase, splicing assay, RNA analysis, or protein studies) was found for this variant. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional assay data identified in the literature
  • No splicing assay or RNA analysis reported for c.371-1G>A
  • Gene-level functional studies do not substitute for variant-level PS3 evidence
Still missing
  • RNA splicing assay would be needed to confirm aberrant splicing in patient cells
  • No functional characterization of this variant in peer-reviewed literature
PP5 ClinVar entry (variation ID 1067789) classifies this variant as Likely pathogenic under a single submitter (Labcorp Genetics/Invitae) with review status 'criteria provided, single submitter' (1-star). PP5 requires a pathogenic classification from a reputable source, typically an expert panel (3-star) or multiple concordant submitters. A single 1-star submission does not meet the PP5 threshold under generic ACMG/AMP 2015. Additionally, the ClinVar record is cataloged under NM_000489.6:c.485-1G>A (different transcript version), flagged as 'no_exact_match' by the pipeline, adding further uncertainty to direct citation. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely pathogenic
  • criteria provided
  • single submitter (1-star)
  • Submitter: Labcorp Genetics/Invitae (SCV001576889)
  • Review status does not meet PP5 threshold (requires 3-star expert panel or multiple concordant submitters)
  • Transcript version discrepancy: ClinVar record listed as NM_000489.6:c.485-1G>A (no_exact_match)
Still missing
  • No 3-star expert panel review or multiple concordant submitters in ClinVar
Sources
clinvar ↗
BA1 This variant is absent from gnomAD-Canada v1.0. The allele frequency does not exceed the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD-Canada v1.0 (AF = 0.0%)
  • No population database shows allele frequency exceeding 1%
Sources
gnomad_canada ↗
BS1 This variant is absent from gnomAD-Canada v1.0. The allele frequency does not exceed the 0.3% threshold required for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD-Canada v1.0 (AF = 0.0%)
  • No population database shows allele frequency exceeding 0.3%
Sources
gnomad_canada ↗
BP4 Multiple in silico tools predict a deleterious effect rather than a benign effect. SpliceAI predicts complete acceptor loss (max delta 0.99, DS_AL 0.99) and BayesDel returns a deleterious score of 0.83. These predictions are inconsistent with a benign interpretation under BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.99 (acceptor loss 0.99) — predicts deleterious splice disruption
  • BayesDel score 0.83 — predicts deleterious
  • No in silico tool predicts benign effect
Sources
spliceai ↗bayesdel
BP6 The only ClinVar classification for this variant is Likely pathogenic (not benign or likely benign). BP6 requires a reputable source to report the variant as benign. No benign classification exists in ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is Likely pathogenic (single submitter)
  • No benign or likely benign classification in ClinVar
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo data available for this variant in the case materials. Details ▾Hide ▴
Still missing
  • De novo confirmation requires parental testing data
PS4 Insufficient proband count data. The variant is reported in ClinVar by a single clinical laboratory (Labcorp Genetics/Invitae) as Likely pathogenic, but individual case counts and detailed phenotype descriptions are not available in the case materials. No case-control enrichment data is present. Details ▾Hide ▴
Evidence considered
  • Single clinical laboratory submission (Labcorp Genetics/Invitae
  • SCV001576889) with Likely pathogenic classification
  • No individual proband count or phenotype details available
Still missing
  • Proband count and phenotype details from submitting laboratory
  • Case-control enrichment data if available
Sources
clinvar ↗
PM1 Insufficient information to determine whether this splice site falls within a critical functional domain or established mutational hotspot in ATRX. The variant disrupts the splice acceptor of intron 5 (exon 6 boundary). Cancerhotspots.org did not identify a significant hotspot at the affected region, and available literature does not provide domain-level characterization specific to this splice junction. PM1 is not applied at this time. Details ▾Hide ▴
Evidence considered
  • No significant cancer hotspot identified at the affected splice region
  • No domain-specific mutational hotspot data in available literature
Still missing
  • Domain-level characterization of ATRX exon 5-6 junction region
  • Review of ATRX domain architecture to determine if this region constitutes a critical functional domain
PM6 No de novo data available for this variant. PM6 requires confirmation of de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
  • Parental testing data required for de novo assessment
PP1 No segregation data available in the case materials. PP1 requires cosegregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • Family segregation data not available
PP4 No proband phenotype data available in the case materials for specificity assessment. PP4 requires that the proband's phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Still missing
  • Proband phenotype details not provided
BS2 No data available on observation of this variant in healthy adult controls. BS2 requires documented observation in a healthy adult individual, particularly for fully penetrant disorders. Details ▾Hide ▴
Still missing
  • No healthy adult control data available
BS3 No functional studies demonstrating a neutral or benign effect for this variant are available. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. Details ▾Hide ▴
Still missing
  • No benign functional evidence identified
BS4 No segregation data available demonstrating lack of cosegregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members. Details ▾Hide ▴
Still missing
  • Family segregation data not available
BP2 No data available on observation of this variant in trans with a known pathogenic variant. BP2 requires documented co-occurrence in trans with a pathogenic variant in a gene associated with a recessive disorder. Details ▾Hide ▴
Still missing
  • No trans observation data available
BP5 No data available on a case with this variant where an alternative molecular basis for disease was identified. BP5 requires that the variant is observed in a case with an alternate molecular cause. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AIntronic splice site variant; no missense comparator at the same residue position is applicable. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per directive — ATR-X syndrome is X-linked, not recessive; PM3 (in trans with pathogenic variant) does not apply. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per directive — this is a splice site variant, not an in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AIntronic splice site variant with no protein residue context; PM5 requires a different pathogenic missense change at the same residue, which is not applicable to splice site variants. The automated PM5 candidate harvest also returned no candidates. Details ▾Hide ▴
Evidence considered
  • No protein residue context available for splice site variant
  • Automated PM5 candidate harvest returned zero same-residue candidates
Sources
pm5_candidates
PP2 N/ASplice site (non-missense) variant; PP2 applies only to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is low. Not applicable to this variant type. Details ▾Hide ▴

No further detail was recorded.

PP3 N/ACanonical splice site variant with PVS1 already applied. Per ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 for the same splice-effect prediction evidence. SpliceAI predicts a deleterious effect (max delta 0.99, acceptor loss 0.99) and BayesDel adds deleterious at 0.83, but this in silico evidence is already captured by the PVS1 assessment of the splice disruption. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.99 (acceptor loss 0.99
  • donor loss 0.78)
  • BayesDel score 0.83 (deleterious)
  • PP3 not stacked with PVS1 per PMC6185798 guidance for canonical splice variants
Sources
spliceai ↗bayesdelpvs1_generic_framework
BP1 N/ASplice site (predicted truncating/non-missense) variant; BP1 applies to missense variants in genes where truncating variants are the primary known disease mechanism. Not applicable to this variant type. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per directive — this is a splice site variant, not an in-frame indel in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ASplice site variant with strong splice effect predictions. BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This variant directly disrupts the canonical splice acceptor consensus, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • c.371-1G>A disrupts canonical splice acceptor consensus sequence
  • SpliceAI predicts strong deleterious effect (max delta 0.99)
Sources
spliceai ↗
PS5 N/AIntronic splice site variant; PS5 requires a different pathogenic nucleotide change at the same codon producing a different amino acid substitution. This semantics is not applicable to splice site variants. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
ATRX
Transcript
NM_000489.5
Coding (HGVS c.)
NM_000489.5:c.371-1G>A
Protein (HGVS p.)
NP_000480.3:p.?
GRCh38
chrX:77693938 C>T
GRCh37
chrX:76949427 C>T
ClinVar
1067789

Gene diagram

Every interpreted variant in ATRX, mapped onto the exon structure of NM_000489.5. Select a row to find it on the plot.

ATRXNM_000489.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -1 bp
0.990
SpliceAI acceptor gainat -7 bp
0.090
SpliceAI donor lossat -114 bp
0.780
SpliceAI donor gainat +30 bp
0.000
Pangolin splice lossmagnitude shown
-0.870
Pangolin splice gain
0.370

Other predictors

REVEL
Not available
BayesDel
0.830

How the predictions were used

BP4 Multiple in silico tools predict a deleterious effect rather than a benign effect. SpliceAI predicts complete acceptor loss (max delta 0.99, DS_AL 0.99) and BayesDel returns a deleterious score of 0.83. These predictions are inconsistent with a benign interpretation under BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.99 (acceptor loss 0.99) — predicts deleterious splice disruption
  • BayesDel score 0.83 — predicts deleterious
  • No in silico tool predicts benign effect
Sources
spliceai ↗bayesdel
PP3 N/ACanonical splice site variant with PVS1 already applied. Per ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked with PVS1 for the same splice-effect prediction evidence. SpliceAI predicts a deleterious effect (max delta 0.99, acceptor loss 0.99) and BayesDel adds deleterious at 0.83, but this in silico evidence is already captured by the PVS1 assessment of the splice disruption. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.99 (acceptor loss 0.99
  • donor loss 0.78)
  • BayesDel score 0.83 (deleterious)
  • PP3 not stacked with PVS1 per PMC6185798 guidance for canonical splice variants
Sources
spliceai ↗bayesdelpvs1_generic_framework
BP7 N/ASplice site variant with strong splice effect predictions. BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This variant directly disrupts the canonical splice acceptor consensus, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • c.371-1G>A disrupts canonical splice acceptor consensus sequence
  • SpliceAI predicts strong deleterious effect (max delta 0.99)
Sources
spliceai ↗

Statement

In silico

In progress — evidence not uploaded yet.

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation.
    Howard MT et al. · 2004
    No paper-specific finding is recorded.
    PMID 15591283 ↗
  • Splicing in action: assessing disease causing sequence changes.
    Baralle D et al. · 2005
    No paper-specific finding is recorded.
    PMID 16199547 ↗
  • Alpha-Thalassemia X-Linked Intellectual Disability Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301622 ↗
  • Neuroradiologic features in X-linked α-thalassemia/mental retardation syndrome.
    Wada T et al. · 2013
    No paper-specific finding is recorded.
    PMID 23681356 ↗
  • Utility of genetic work-up for 46, XY patients with severe hypospadias.
    Srivastava P et al. · 2023
    No paper-specific finding is recorded.
    PMID 36496321 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

SpliceAI Lookup Recorded maximum delta 0.990 Open source ↗
ClinVar 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

In progress — evidence not uploaded yet.

In silico

In progress — evidence not uploaded yet.

Functional

In progress — evidence not uploaded yet.

Somatic

In progress — evidence not uploaded yet.

Literature

In progress — evidence not uploaded yet.