Classification rationale

BS1BP4 Likely Benign

MET c.110T>C

The MET c.110T>C (p.Val37Ala) variant has been reported in ClinVar with likely benign and benign submissions.¹ This variant is present in population databases at a frequency above the BS1 threshold, with the highest observed frequency of 0.70588% in South Asian individuals in gnomAD v2.1 and 0.68732% in South Asian individuals in gnomAD v4.1, arguing against a rare pathogenic germline variant.² No well-established variant-specific functional study was identified to support either a damaging or a normal effect.³ Computational evidence supports a benign interpretation, with SpliceAI predicting no significant splice impact (maximum delta score 0.00), REVEL of 0.142, and BayesDel of -0.247812.⁴

BS1 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗

4 spliceai ↗revelbayesdel

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.

Gene diagram · NM_001127500.3 · variants mapped to exon structure

MET NM_001127500.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

Population frequency is above the 0.3% BS1 threshold. The highest observed frequency is 0.70588% in gnomAD v2.1 South Asian individuals and 0.68732% in gnomAD v4.1 South Asian individuals, which argues against a rare pathogenic germline variant.

gnomAD v2.1 South Asian AF 0.00705882 (216/30600)1 homozygote.gnomAD v4.1 South Asian AF 0.00687323 (626/91078)

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Multiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.142, and BayesDel is -0.247812, which together support a benign computational interpretation.

SpliceAI max delta score 0.00.REVEL score 0.142.BayesDel score -0.247812.

spliceai ↗

Assessed · not applied · 5 not met · 12 not assessed

Pathogenic

PS1 No reviewed evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic classification.

PS2 No confirmed de novo occurrence with verified parentage was identified for this variant.

PS3 No well-established functional study demonstrating a damaging effect of this specific variant was identified.

PS4 Available evidence does not show enrichment of this variant in affected individuals compared with population databases.

PM1 This variant is not supported to lie in a well-established mutational hotspot or critical functional domain without benign variation.

PM2 Population frequency is not low enough for PM2.

PM6 No presumed de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish that this gene has a low rate of benign missense variation and that missense variation is the predominant mechanism required for PP2 application in this case.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No phenotype-specific evidence was provided to show that the clinical presentation is highly specific for a disorder caused by this gene.

Benign

BA1 Population frequency does not reach the 1% BA1 threshold.

BS2 Although this variant is observed in population databases, the available evidence was not sufficient to apply BS2 on the basis of observation in unaffected individuals alone.

BS3 No well-established functional study demonstrating normal function of this specific variant was identified.

BS4 No family data were identified showing lack of segregation of this variant with disease.

BP2 No phase information was identified to show this variant occurring in trans with a pathogenic variant or in cis with another variant in a way that supports BP2.

BP5 No alternate molecular diagnosis or other established cause of disease was provided that would support BP5.

N/A · 9 PVS1 · PM3 · PM4 · PM5 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000544625; MAF= 0.05446%, 879/1613956 alleles, homozygotes = 10) and has highest observed frequency in the South Asian population (AF= 0.00687323; MAF= 0.68732%, 626/91078 alleles, homozygotes = 10); grpmax FAF= 0.00642681.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000908223; MAF= 0.09082%, 255/280768 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00705882; MAF= 0.70588%, 216/30600 alleles, homozygotes = 1); grpmax FAF= 0.0062877.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.054% · 879 / 1,613,956
10 hom · FAF 0.64%

South Asian 626 / 91,078	0.69% 10 hom
Middle Eastern 9 / 6,060	0.15%
Ashkenazi Jewish 36 / 29,600	0.12%
Remaining individuals 46 / 62,496	0.074%
European (non-Finnish) 157 / 1,179,916	0.013%
Admixed American 3 / 59,978	0.005%
African/African American 2 / 75,022	0.0027%

+ 3 not observed (European (Finnish), Amish, East Asian)

gnomAD v2.1

0.091% · 255 / 280,768
1 hom · FAF 0.63%

South Asian 216 / 30,600	0.71% 1 hom
Ashkenazi Jewish 11 / 10,358	0.11%
Remaining individuals 4 / 7,146	0.056%
European (non-Finnish) 23 / 128,602	0.018%
African/African American 1 / 24,190	0.0041%

+ 3 not observed (Admixed American, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (3 clinical laboratories). (ClinVarID = 41610)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.142. BayesDel score = -0.247812.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MET, a receptor tyrosine kinase, is recurrently altered by mutation or amplification in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104627100, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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