NM_001127500.3:c.156_157delinsTT is a nonsense variant (p.Gln53Ter) predicted to result in premature termination at codon 53 of 1409 amino acids with expected nonsense-mediated mRNA decay. MET loss of function is an established germline disease mechanism for osteofibrous dysplasia (PVS1).1 The variant is absent from gnomAD v2.1 and v4.1 population databases, supporting rarity in the general population (PM2).2 No functional studies, segregation data, de novo observations, ClinVar classifications, or variant-specific publications were identified for this variant. All remaining pathogenic and benign criteria were not met or not applicable. Under the generic ACMG/AMP 2015 classification rules (Richards et al. 2015), the combination of PVS1 (very strong) + PM2 (moderate) meets the threshold for Likely Pathogenic (1 Very Strong + 1 Moderate).3
MET
Final classification
Likely Pathogenic
MET c.156_157delinsTT · p.Gln53Ter
MET
NM_001127500.3:c.156_157delinsTT is a nonsense variant (p.Gln53Ter) predicted to result in premature termination at codon 53 of 1409 amino acids with expected nonsense-mediated mRNA decay. MET loss of function is an established germline disease mechanism for osteofibrous dysplasia (PVS1).
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.
Classification rationale
PVS1PM2
Likely Pathogenic
MET c.156_157delinsTT
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_context
3
generic_acmg_combination_rules
Gene diagram
· NM_001127500.3 · variants mapped to exon structure
MET
NM_001127500.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_001127500.3:c.156_157delinsTT is a nonsense variant (NP_001120972.1:p.(Gln53Ter)) predicted to result in premature termination at codon 53 of 1409 amino acids, with expected nonsense-mediated mRNA decay (NMD). MET loss of function is an established germline disease mechanism (osteofibrous dysplasia; PMID:26637977). Under the ClinGen SVI PVS1 recommendations (PMC6185798), this early-truncating nonsense variant in exon 2 of 21 qualifies for PVS1 at default strength in a gene where LOF is a known mechanism.
Nonsense variant p.Gln53Ter at codon 53 of 1409 — early truncation with expected NMDMET loss of function is an established germline disease mechanism for osteofibrous dysplasiaClinGen SVI PVS1 framework (PMC6185798) supports PVS1 for nonsense variants in LOF-intolerant genes
✓
PM2
moderate
Pathogenic
NM_001127500.3:c.156_157delinsTT is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases under the generic ACMG/AMP framework.
Absent from gnomAD v2.1 (AF = 0.0)Absent from gnomAD v4.1 (AF = 0.0)Absent from gnomAD-Canada v1.0
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant resulting in the same amino acid change (p.Gln53Ter) via a different nucleotide change has been identified.
PS2
No de novo occurrence data are available for this variant.
PS3
No variant-specific functional studies were identified for NM_001127500.3:c.156_157delinsTT.
PS4
No case-control studies or enriched cohort data are available for this variant.
PM1
The variant produces a premature termination codon at position 53, removing the vast majority of the MET protein including all annotated functional domains (SEMA, PSI, IPT, transmembrane, and kinase domains).
PM5
No ClinVar-listed pathogenic missense variant at the same residue (Gln53) was identified.
PM6
No confirmed de novo observation was identified for this variant in any publication or clinical database.
PP1
No segregation data are available for this variant.
PP4
No patient phenotype data are available for this variant.
PP5
This variant is absent from ClinVar.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1.
BS1
The variant is absent from gnomAD.
BS2
No data are available regarding observation of this variant in healthy adult individuals.
BS3
No functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No segregation data are available for this variant.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant.
BP5
No alternative molecular basis for disease has been identified in any reported case carrying this variant.
BP6
This variant is absent from ClinVar.
N/A · 8
PM3 · PM4 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links