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ATRXc.5698-1G>CLikely pathogenic
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Variant interpretation report

ATRX c.5698-1G>C, p.?

NM_000489.5:c.5698-1G>C NP_000480.3:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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

NM_000489.5:c.5698-1G>C disrupts the canonical splice acceptor site (AG) at intron 23. ATRX loss of function is an established disease mechanism for ATR-X syndrome (MIM #301040) and associated cancer predisposition. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with an established loss-of-function disease mechanism qualify for PVS1 at very strong strength. NM_000489.5 is the RefSeq select transcript, biologically relevant. The variant is absent from gnomAD, consistent with a pathogenic splice variant. PP3 is not stacked for the same splice-prediction evidence per PVS1 framework guidance.

PM2Moderate
PM2 · moderate

NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868), complete absence from large population cohorts meets PM2 at moderate strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

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
0.860 maximum delta

Recorded SpliceAI maximum delta score: 0.860. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64881768, n = 2 times).

Context only COSMIC ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at very strong strength: NM_000489.5:c.5698-1G>C disrupts the canonical splice acceptor site at intron 23. ATRX loss of function is an established disease mechanism for ATR-X syndrome. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in LOF-established genes receive PVS1 at very strong strength.

PM2 is met at moderate strength: this variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Complete absence from large population cohorts meets PM2 at moderate strength under generic ACMG/AMP 2015.

No benign criteria are met. Computational evidence (SpliceAI max delta 0.86, BayesDel 0.83) predicts a deleterious splicing effect, consistent with the PVS1 determination. PP3 is not applied independently per PVS1 framework guidance against double-counting splice prediction evidence.

Overall classification: Likely Pathogenic. The combination of PVS1 (very strong) and PM2 (moderate) meets the Likely Pathogenic threshold under generic ACMG/AMP 2015 combination rules (1 Very Strong + 1 Moderate).

Met · 2

PVS1 Very strongNM_000489.5:c.5698-1G>C disrupts the canonical splice acceptor site (AG) at intron 23. ATRX loss of function is an established disease mechanism for ATR-X syndrome (MIM #301040) and associated cancer predisposition. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with an established loss-of-function disease mechanism qualify for PVS1 at very strong strength. NM_000489.5 is the RefSeq select transcript, biologically relevant. The variant is absent from gnomAD, consistent with a pathogenic splice variant. PP3 is not stacked for the same splice-prediction evidence per PVS1 framework guidance. Details ▾Hide ▴
Evidence considered
  • Canonical splice acceptor site disrupted at intron 23 (c.5698-1G>C
  • AG→AC)
  • SpliceAI max delta score 0.86 (acceptor loss DS_AL=0.86
  • donor loss DS_DL=0.81)
  • ATRX loss of function is established germline disease mechanism for ATR-X syndrome
  • NM_000489.5 is RefSeq select transcript
  • biologically relevant
  • Absent from gnomAD v2.1 and v4.1
  • consistent with highly penetrant pathogenic variant
Still missing
  • No RNA studies confirming aberrant splicing for this specific variant
  • No NMD prediction confirmed for the resulting transcript
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentspliceai ↗gnomad_v2 ↗gnomad_v4 ↗
PM2 ModerateNM_000489.5:c.5698-1G>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Under the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868), complete absence from large population cohorts meets PM2 at moderate strength. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles observed)
  • Absent from gnomAD v4.1 (0 alleles observed)
  • Absent from gnomAD-Canada v1.0 (0 alleles observed)
Still missing
  • Coverage at this locus in gnomAD not confirmed from screenshots
  • absent calls assume adequate coverage
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo observations have been reported for NM_000489.5:c.5698-1G>C in the literature or ClinVar. Details ▾Hide ▴
Still missing
  • No trio or parent-of-origin data available for this variant
PS3 No well-established functional studies (in vitro or in vivo) have been identified demonstrating a deleterious effect for NM_000489.5:c.5698-1G>C. Details ▾Hide ▴
Still missing
  • No RNA studies
  • minigene assays
  • or protein function assays available for this variant
PS4 No case-control or cohort enrichment data are available for this variant. The variant has not been reported in affected individuals in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no affected individual reports available
Still missing
  • No prevalence data in ATR-X syndrome or related phenotype cohorts
Sources
clinvar ↗
PM1 This variant does not localize to a recognized mutational hotspot or critical functional domain within ATRX for which pathogenic enrichment has been established. Hotspot analysis did not identify this residue or region as significantly enriched for pathogenic variation. Details ▾Hide ▴
Evidence considered
  • No hotspot signal identified for this splice position or surrounding region
Still missing
  • No gene-specific domain-level pathogenic enrichment map available for ATRX
PM6 No de novo observations (with or without confirmed paternity) have been reported for NM_000489.5:c.5698-1G>C. Details ▾Hide ▴
Still missing
  • No trio sequencing data available for this variant
PP1 No co-segregation data are available for NM_000489.5:c.5698-1G>C in affected families. Details ▾Hide ▴
Still missing
  • No family studies or segregation analysis published for this variant
PP3 SpliceAI predicts a deleterious effect on splicing (max delta 0.86, acceptor loss DS_AL=0.86). However, per ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked for the same splice-effect prediction evidence already captured by PVS1 when assessing canonical splice variants. The in silico splice evidence is incorporated into the PVS1 determination. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 (acceptor loss DS_AL=0.86
  • donor loss DS_DL=0.81)
  • BayesDel score 0.83 (damaging prediction)
Sources
spliceai ↗pvs1_variant_assessment
PP4 No patient phenotype or detailed clinical data are available for independent assessment of phenotype specificity. The variant has not been reported in ClinVar with associated phenotype information. Details ▾Hide ▴
Still missing
  • No proband phenotype or clinical history available for review
Sources
clinvar ↗
PP5 No reputable source (e.g., clinical diagnostic laboratory) has reported NM_000489.5:c.5698-1G>C as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no submitter classifications available
Sources
clinvar ↗
BA1 NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1 and v4.1 population databases. The allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD
  • does not exceed 1% BA1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_000489.5:c.5698-1G>C is absent from gnomAD v2.1 and v4.1 population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3% under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD
  • does not exceed 0.3% BS1 threshold
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available regarding observation of NM_000489.5:c.5698-1G>C in healthy adults. The variant is absent from all queried population databases. Details ▾Hide ▴
Still missing
  • No healthy adult cohort specifically screened for this variant
BS3 No well-established functional studies demonstrating no deleterious effect for NM_000489.5:c.5698-1G>C have been identified. Details ▾Hide ▴
Still missing
  • No RNA studies
  • minigene assays
  • or protein function assays demonstrating normal splicing
BS4 No segregation data are available to evaluate lack of segregation with disease for NM_000489.5:c.5698-1G>C. Details ▾Hide ▴
Still missing
  • No family studies available to assess non-segregation
BP2 No data are available regarding observation of NM_000489.5:c.5698-1G>C in trans with a known pathogenic ATRX variant. Details ▾Hide ▴
Still missing
  • No co-occurrence or phase data available
BP4 Multiple lines of computational evidence predict a deleterious effect on splicing. SpliceAI predicts acceptor loss (DS_AL=0.86, max delta 0.86) and donor loss (DS_DL=0.81). BayesDel score of 0.83 also predicts a damaging effect. These computational predictions do not support BP4 (no impact on gene product). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 predicts splicing disruption
  • not absence of impact
  • BayesDel score 0.83 (damaging prediction)
Sources
spliceai ↗bayesdel
BP5 No alternative molecular basis for disease has been identified in an individual carrying NM_000489.5:c.5698-1G>C. No cases with this variant and an alternative genetic cause have been reported. Details ▾Hide ▴
Still missing
  • No cases reported with this variant to evaluate for alternative molecular etiology
BP6 No reputable source has classified NM_000489.5:c.5698-1G>C as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no benign classifications available
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid change as an established pathogenic missense variant. This is a canonical splice variant with no amino acid substitution predicted. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to a novel missense change at the same amino acid residue as an established pathogenic missense variant. This is a canonical splice variant with no missense residue context. PM5 candidate collection confirmed no same-residue comparator variants are applicable. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This is a canonical splice variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a canonical splice variant expected to cause loss of function, not a missense change. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a canonical splice variant with strong SpliceAI evidence of splicing disruption (max delta 0.86). Details ▾Hide ▴
Sources
spliceai ↗
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. No applicable framework. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
ATRX
Transcript
NM_000489.5
Coding (HGVS c.)
NM_000489.5:c.5698-1G>C
Protein (HGVS p.)
NP_000480.3:p.?
GRCh38
chrX:77599821 C>G
GRCh37
chrX:76855290 C>G
COSMIC
COSV64881768

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 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -1 bp
0.860
SpliceAI acceptor gainat +180 bp
0.070
SpliceAI donor lossat -89 bp
0.810
SpliceAI donor gainat +48 bp
0.020
Pangolin splice lossmagnitude shown
-0.850
Pangolin splice gain
0.040

Other predictors

REVEL
Not available
BayesDel
0.830

How the predictions were used

PP3 SpliceAI predicts a deleterious effect on splicing (max delta 0.86, acceptor loss DS_AL=0.86). However, per ClinGen SVI PVS1 recommendations (PMC6185798), PP3 should not be stacked for the same splice-effect prediction evidence already captured by PVS1 when assessing canonical splice variants. The in silico splice evidence is incorporated into the PVS1 determination. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 (acceptor loss DS_AL=0.86
  • donor loss DS_DL=0.81)
  • BayesDel score 0.83 (damaging prediction)
Sources
spliceai ↗pvs1_variant_assessment
BP4 Multiple lines of computational evidence predict a deleterious effect on splicing. SpliceAI predicts acceptor loss (DS_AL=0.86, max delta 0.86) and donor loss (DS_DL=0.81). BayesDel score of 0.83 also predicts a damaging effect. These computational predictions do not support BP4 (no impact on gene product). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.86 predicts splicing disruption
  • not absence of impact
  • BayesDel score 0.83 (damaging prediction)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a canonical splice variant with strong SpliceAI evidence of splicing disruption (max delta 0.86). Details ▾Hide ▴
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.86). BayesDel score = 0.83.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.860 Open source ↗
ClinVar Captured ClinVar source record 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 v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.86). BayesDel score = 0.83.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV64881768, n = 2 times).