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ALKc.3373G>AUncertain significance
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Variant interpretation report

ALK c.3373G>A, p.(Gly1125Ser)

NM_004304.4:c.3373G>A NP_004295.2:p.(Gly1125Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ALK

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
PM2Supporting
PM2 · supporting

NM_004304.4:c.3373G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP threshold for PM2 (allele frequency <0.1% or absent).

PP3Supporting
PP3 · supporting

In silico predictors support a deleterious effect: REVEL score 0.968 (above the 0.932 threshold commonly used for PP3) and BayesDel score 0.576 (above the 0.5 damaging threshold). SpliceAI predicts no splice impact (max delta 0.00).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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, PP3 supporting; combination = 2 supporting, which maps to VUS.

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 · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
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. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma

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.

29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 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_004304.4:c.3373G>A (p.Gly1125Ser) is a missense variant in exon 21 of ALK, residing within the tyrosine kinase domain P-loop (GAFGE motif). It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at the supporting level.

In silico predictors support a deleterious effect: REVEL score 0.968 (strongly damaging) and BayesDel score 0.576 (damaging), meeting PP3 at the supporting level. SpliceAI predicts no splice impact (max delta 0.00).

No variant-specific functional data, de novo reports, segregation data, or case-control studies are available. The variant is absent from ClinVar, COSMIC, and cancerhotspots.org. OncoKB classifies it as 'Unknown Oncogenic Effect'.

With two supporting criteria (PM2_supporting + PP3_supporting) and no criteria met at moderate, strong, or benign levels, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 generic classification rules (PMID:25741868).

Met · 2

PM2 SupportingNM_004304.4:c.3373G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP threshold for PM2 (allele frequency <0.1% or absent). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingIn silico predictors support a deleterious effect: REVEL score 0.968 (above the 0.932 threshold commonly used for PP3) and BayesDel score 0.576 (above the 0.5 damaging threshold). SpliceAI predicts no splice impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL 0.968 (damaging).
  • BayesDel 0.576 (damaging).
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 No alternate nucleotide change at c.3373 resulting in the same amino acid change has been identified as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No same-amino-acid pathogenic comparator identified.
Still missing
  • No known pathogenic variant at the same position with a different nucleotide change.
Sources
clinvar ↗
PS2 No de novo occurrence data are available for this variant; no family studies have been identified. Details ▾Hide ▴
Still missing
  • No family or de novo studies available.
PS3 No variant-specific functional data have been identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional evidence. No experimental studies of NM_004304.4:c.3373G>A or a systematically characterized range encompassing Gly1125 were found in the literature. Details ▾Hide ▴
Evidence considered
  • OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.
Still missing
  • No functional studies of p.Gly1125Ser or systematic range characterization available.
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available. Details ▾Hide ▴
Still missing
  • No prevalence or case-control data available.
PM1 Although Gly1125 resides within the ALK tyrosine kinase domain P-loop (GAFGE motif, aa 1125-1129), cancerhotspots.org does not identify this residue as a statistically significant hotspot, and no literature establishes that missense variants in the ALK kinase domain are a common mechanism of germline disease. Domain-level knowledge is insufficient for PM1 in the absence of enrichment-based or residue-specific evidence. Details ▾Hide ▴
Evidence considered
  • Not a cancer hotspot
  • no domain-level PM1 framework available for ALK missense variants.
Still missing
  • No domain-specific missense enrichment data for ALK germline disease.
PM6 No de novo occurrence data are available; no family studies or trio sequencing reports were identified. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP2 No missense constraint data (Z-score, missense depletion metrics) are available for ALK to assess whether the gene has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • No missense constraint data available for ALK.
Still missing
  • Missense constraint metrics not available.
PP4 No patient phenotype information is available to assess specificity for an ALK-related disorder. Details ▾Hide ▴
Still missing
  • No phenotype data available.
PP5 No reputable source (ClinVar, diagnostic laboratory) has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Still missing
  • No source reporting variant as pathogenic.
Sources
clinvar ↗
BA1 NM_004304.4:c.3373G>A is absent from all gnomAD datasets; allele frequency does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 NM_004304.4:c.3373G>A is absent from all gnomAD datasets; allele frequency does not exceed the non-VCEP BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data are available demonstrating this variant has been observed in a healthy adult individual for a fully penetrant disorder. Details ▾Hide ▴
Still missing
  • No healthy adult observation data available.
BS3 No well-established in vitro or in vivo functional studies demonstrate that this variant has no deleterious effect on protein function or splicing. Details ▾Hide ▴
Still missing
  • No benign functional evidence available for this variant.
BS4 No family segregation data are available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP1 ALK has well-established pathogenic missense variants (e.g., p.Arg1275Gln in neuroblastoma predisposition), so a missense variant does not qualify for BP1, which requires that primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
  • ALK has known pathogenic germline missense variants (e.g.
  • R1275Q).
BP2 No data are available to demonstrate this variant has been observed in trans with a known pathogenic variant in ALK. Details ▾Hide ▴
Still missing
  • No trans configuration data available.
BP4 In silico predictors do not support a benign effect; REVEL score of 0.968 is strongly damaging, and BayesDel score of 0.576 is above the damaging threshold. Details ▾Hide ▴
Evidence considered
  • REVEL 0.968 (damaging) does not support BP4.
  • BayesDel 0.576 (damaging) does not support BP4.
Sources
revelbayesdel
BP5 No evidence that this variant was found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate-cause data available.
BP6 No reputable source has classified this variant as benign; the variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar.
Sources
clinvar ↗
PS5 No alternate missense change at codon 1125 has been reported as pathogenic in ClinVar or the literature. PM5 candidate review found no same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • No pathogenic comparator variants at residue Gly1125 identified.
Still missing
  • No known pathogenic variants at codon 1125.
Sources
pm5_candidates
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004304.4:c.3373G>A is a missense substitution (p.Gly1125Ser); it does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANo recessive inheritance data available; ALK germline disease is not known to follow a recessive pattern. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ANo protein-length change; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue, same-reference-amino-acid comparator variants were identified in ClinVar; PM5 automatic candidate harvesting was unable to find eligible comparators. Details ▾Hide ▴
Evidence considered
  • Zero same-residue candidates found
  • PM5 not applicable.
Sources
pm5_candidates
BP3 N/AIn-frame indel rule not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_004304.4:c.3373G>A is a missense variant (p.Gly1125Ser), not synonymous or intronic; BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 not applicable.

Identifiers

Gene
ALK
Transcript
NM_004304.4
Coding (HGVS c.)
NM_004304.4:c.3373G>A
Protein (HGVS p.)
NP_004295.2:p.(Gly1125Ser)
GRCh38
chr2:29222594 C>T
GRCh37
chr2:29445460 C>T

Gene diagram

Every interpreted variant in ALK, mapped onto the exon structure of NM_004304.4. Select a row to find it on the plot.

ALKNM_004304.4
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 -213 bp
0.000
SpliceAI acceptor gainat -2 bp
0.000
SpliceAI donor lossat +135 bp
0.000
SpliceAI donor gainat -250 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.968
BayesDel
0.576

How the predictions were used

PP3 SupportingIn silico predictors support a deleterious effect: REVEL score 0.968 (above the 0.932 threshold commonly used for PP3) and BayesDel score 0.576 (above the 0.5 damaging threshold). SpliceAI predicts no splice impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL 0.968 (damaging).
  • BayesDel 0.576 (damaging).
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP4 In silico predictors do not support a benign effect; REVEL score of 0.968 is strongly damaging, and BayesDel score of 0.576 is above the damaging threshold. Details ▾Hide ▴
Evidence considered
  • REVEL 0.968 (damaging) does not support BP4.
  • BayesDel 0.576 (damaging) does not support BP4.
Sources
revelbayesdel
BP7 N/ANM_004304.4:c.3373G>A is a missense variant (p.Gly1125Ser), not synonymous or intronic; BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.968. BayesDel score = 0.575979.

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 0.000 Open source ↗
ClinVar Captured ClinVar source record 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

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.968. BayesDel score = 0.575979.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma

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.