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ATRXc.7315C>ALikely benign
Print report
Variant interpretation report

ATRX c.7315C>A, p.(Pro2439Thr)

NM_000489.5:c.7315C>A NP_000480.3:p.(Pro2439Thr) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000489.5:c.7315C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2. Note: ATRX is X-linked, and gnomAD population frequency interpretation requires consideration of hemizygous male ascertainment.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score is -0.166588 (benign-range prediction below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing alteration), and REVEL is unavailable. The aggregate in silico prediction is consistent with a benign interpretation.

BP6Supporting
BP6 · supporting

A reputable clinical testing laboratory (Invitae/Labcorp) has reported this variant as Likely benign in ClinVar (SCV002431510, criteria provided, single submitter). Caution: the ClinVar match was to NM_000489.6(ATRX):c.7429C>A (p.Pro2477Thr), a different transcript version, rather than the queried NM_000489.5:c.7315C>A. The two transcript versions likely represent the same genomic variant, but exact equivalence was not confirmed by the ClinVar audit. This classification reflects a single-submitter, non-expert-panel assertion.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign, BP6 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 3 met · 3 not met · 16 not assessed · 4 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

NM_000489.5:c.7315C>A (p.Pro2439Thr) is a missense variant in exon 35 of the ATRX gene. This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).

Multiple lines of computational evidence suggest no deleterious effect: BayesDel score of -0.166588 is in the benign range, and SpliceAI predicts no splicing impact (max delta = 0.00) (BP4_Supporting).

A clinical testing laboratory (Invitae/Labcorp) has classified this variant as Likely benign in ClinVar (SCV002431510, criteria provided, single submitter) (BP6_Supporting). Caution: the ClinVar record matched to a different transcript version (NM_000489.6:c.7429C>A vs NM_000489.5:c.7315C>A), though these likely represent the same genomic variant.

Under generic ACMG/AMP 2015 classification rules (PMID:25741868), the combination of two supporting benign criteria (BP4, BP6) meets the threshold for Likely Benign, despite one supporting pathogenic criterion (PM2).

Met · 3

PM2 SupportingNM_000489.5:c.7315C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2. Note: ATRX is X-linked, and gnomAD population frequency interpretation requires consideration of hemizygous male ascertainment. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. BayesDel score is -0.166588 (benign-range prediction below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing alteration), and REVEL is unavailable. The aggregate in silico prediction is consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.166588 (benign-range)
  • SpliceAI: max delta 0.00
  • no deleterious in silico prediction.
Still missing
  • REVEL score not available for X-chromosome variant.
Sources
bayesdelspliceai ↗
BP6 SupportingA reputable clinical testing laboratory (Invitae/Labcorp) has reported this variant as Likely benign in ClinVar (SCV002431510, criteria provided, single submitter). Caution: the ClinVar match was to NM_000489.6(ATRX):c.7429C>A (p.Pro2477Thr), a different transcript version, rather than the queried NM_000489.5:c.7315C>A. The two transcript versions likely represent the same genomic variant, but exact equivalence was not confirmed by the ClinVar audit. This classification reflects a single-submitter, non-expert-panel assertion. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely benign
  • Labcorp Genetics (Invitae)
  • SCV002431510
  • criteria provided
  • single submitter. Non-exact transcript match (NM_000489.6 vs NM_000489.5).
Still missing
  • Exact transcript version match not confirmed by ClinVar audit
  • NM_000489.6:c.7429C>A vs NM_000489.5:c.7315C>A.
Sources
clinvar ↗

Not met · 3 · evaluated, threshold not reached

PM1 This variant is not located in a statistically significant mutational hotspot as determined by Cancer Hotspots analysis, nor in a well-characterized functional domain where benign variation is absent. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no significant hotspot
  • residue not in statistically recurrent mutation site.
PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score is -0.166588 (below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing impact), and REVEL is unavailable. The aggregate in silico evidence is consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.166588 (benign-range)
  • SpliceAI: max delta 0.00
  • REVEL: not available.
Still missing
  • REVEL score not available for X-chromosome variant.
Sources
bayesdelspliceai ↗
BS1 NM_000489.5:c.7315C>A is absent from gnomAD; the allele frequency does not exceed the 0.3% BS1 threshold for an X-linked disorder. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • AF does not exceed 0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 16 · no assessment recorded

PS1 No evidence of a different nucleotide change at the same amino acid position (Pro2439) that is known to be pathogenic. PM5 candidate search found zero same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants identified in ClinVar.
Still missing
  • No comparator variants available for PS1 determination.
PS2 No de novo observation data available for this variant. No publications report de novo occurrence of NM_000489.5:c.7315C>A. Details ▾Hide ▴
Still missing
  • No de novo data available for this variant.
PS3 No well-established functional studies are available for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with functional data for NM_000489.5:c.7315C>A were identified. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 No case-control data or published patient observations specific to NM_000489.5:c.7315C>A. The GeneReviews article (PMID:20301622) is a general clinical summary of ATR-X syndrome and does not provide variant-specific prevalence data. Details ▾Hide ▴
Still missing
  • No case-control or patient observation data available for this variant.
PM6 No de novo data available for NM_000489.5:c.7315C>A. No publications report assumed de novo occurrence without parental confirmation. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No cosegregation data available for this variant. No family studies have been reported. Details ▾Hide ▴
Still missing
  • No cosegregation data available.
PP2 HCI Prior score is not available for ATRX (gene_not_supported). Cannot calculate the rate of benign missense variation or determine whether missense variants are a common disease mechanism independent of functional domain context. Details ▾Hide ▴
Evidence considered
  • HCI Prior: gene_not_supported
  • no custom PP2 score available.
Still missing
  • No gene-specific missense constraint metric available.
PP4 No phenotypic data have been submitted for this specific case. Cannot assess whether the patient's phenotype or family history is highly specific for ATRX-related disease. Details ▾Hide ▴
Still missing
  • No phenotypic data available for this case.
PP5 No reputable source has reported this variant as pathogenic. The closest ClinVar entry (variation ID 1623753, matched to NM_000489.6:c.7429C>A, a different transcript version) reports Likely benign from a single clinical testing laboratory. This does not satisfy PP5 which requires a pathogenic assertion from a reputable source. Details ▾Hide ▴
Evidence considered
  • ClinVar (non-exact match): Likely benign
  • single submitter.
BS2 No data available regarding observation of this variant in healthy adults for a fully penetrant disorder. No population-based penetrance studies identified. Details ▾Hide ▴
Still missing
  • No healthy-adult observation data available.
BS3 No well-established functional studies are available showing no damaging effect for NM_000489.5:c.7315C>A. OncoKB reports Unknown Oncogenic Effect with no functional annotation. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional annotation.
Still missing
  • No functional studies available.
Sources
oncokb ↗
BS4 No segregation data available for this variant. No family studies have been reported to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP1 ATRX disease mechanism includes both truncating and missense variants. The PVS1 gene context supports loss of function as a germline disease mechanism, but missense variants are also observed in ATRX-related disorders. Without a gene-specific CSPEC/VCEP framework defining variant-type disease architecture, BP1 cannot be confidently applied. Details ▾Hide ▴
Evidence considered
  • ATRX LoF mechanism supported
  • both missense and truncating variants are observed in disease contexts.
Still missing
  • No gene-specific variant-spectrum guidance available.
BP2 No data available regarding observation of NM_000489.5:c.7315C>A in trans with a known pathogenic ATRX variant. ATRX is X-linked; BP2 is generally not applicable for X-linked genes without specific framework guidance. Details ▾Hide ▴
Still missing
  • BP2 applicability uncertain for X-linked gene.
BP5 No data regarding an alternate molecular basis for disease in a case carrying NM_000489.5:c.7315C>A. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
PS5 PS5 is not a standard ACMG/AMP 2015 criterion. No reputable source has reported this variant as pathogenic. The closest ClinVar entry (non-exact transcript version match) reports Likely benign, not pathogenic. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000489.5:c.7315C>A is a missense variant (p.Pro2439Thr) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Pro2439Thr)
  • variant_bucket=other
  • apply_generic_pvs1_framework=false per PVS1 variant assessment.
Sources
pvs1_generic_framework ↗
PM5 N/AUnable to confirm same-residue pathogenic comparator variants for PM5 application. PM5 candidate search identified zero same-residue (Pro2439) comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
  • Zero same-residue comparator variants found in ClinVar.
Sources
pm5_candidates
BA1 N/ANM_000489.5:c.7315C>A is absent from gnomAD; the allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP7 N/ANM_000489.5:c.7315C>A is a missense variant (p.Pro2439Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Identifiers

Gene
ATRX
Transcript
NM_000489.5
Coding (HGVS c.)
NM_000489.5:c.7315C>A
Protein (HGVS p.)
NP_000480.3:p.(Pro2439Thr)
GRCh38
chrX:77508515 G>T
GRCh37
chrX:76763993 G>T
ClinVar
1623753

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

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
-0.167

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. BayesDel score is -0.166588 (benign-range prediction below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing alteration), and REVEL is unavailable. The aggregate in silico prediction is consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.166588 (benign-range)
  • SpliceAI: max delta 0.00
  • no deleterious in silico prediction.
Still missing
  • REVEL score not available for X-chromosome variant.
Sources
bayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score is -0.166588 (below the typical damaging threshold of 0), SpliceAI max delta score is 0.00 (no predicted splicing impact), and REVEL is unavailable. The aggregate in silico evidence is consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.166588 (benign-range)
  • SpliceAI: max delta 0.00
  • REVEL: not available.
Still missing
  • REVEL score not available for X-chromosome variant.
Sources
bayesdelspliceai ↗
BP7 N/ANM_000489.5:c.7315C>A is a missense variant (p.Pro2439Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.166588.

2 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

  • Alpha-Thalassemia X-Linked Intellectual Disability Syndrome.
    Adam MP et al. · 1993
    GeneReviews clinical summary of Alpha-Thalassemia X-Linked Intellectual Disability (ATR-X) Syndrome. Provides general overview of ATRX gene, clinical features, and genetic counseling. NM_000489.5:c.7315C>A (p.Pro2439Thr) was not identified as a reported pathogenic variant in the available abstract metadata.
    Does not name this variant
    PMID 20301622 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological framework paper describing variant classification rules and scoring; it does not report or evaluate individual ATRX variants.
    Does not name this variant
    PMID 28492532 ↗

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 0.000 Open source ↗
ClinVar 1 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB 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

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.166588.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATRX, a tumor suppressor involved in transcriptional regulation, is infrequently altered in cancer.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.