NM_001127500.3:c.156_157delinsTT

MET · NP_001120972.1:p.(Gln53Ter) · NM_001127500.3

GRCh37: chr7:116339294 CC>TT · GRCh38: chr7:116699240 CC>TT

Gene: MET Transcript: NM_001127500.3

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

MET

Transcript

NM_001127500.3

Protein

NP_001120972.1:p.(Gln53Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

The variant is absent from gnomAD v2.1 and v4.1 population databases, supporting rarity in the general population (PM2).

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No established pathogenic variant resulting in the same amino acid change (p.Gln53Ter) via a different nucleotide change has been identified. The variant is absent from ClinVar, and no literature reports an alternative nucleotide change producing the same nonsense codon at position 53.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. No publications or clinical reports documenting a confirmed de novo observation were identified.
PS3	Not met	No variant-specific functional studies were identified for NM_001127500.3:c.156_157delinsTT. The variant has not been directly tested in any experimental assay, nor does it fall within a systematically characterized range in published functional studies. OncoKB classifies this variant as Unknown Oncogenic Effect with no supporting functional evidence.	oncokb
PS4	Not met	No case-control studies or enriched cohort data are available for this variant. The variant is absent from ClinVar with no affected individuals reported.	clinvar
PS5	Not met	No data from an established in vitro or in vivo functional assay show a damaging effect that is specific to the gene and disease context for this variant.
PM1	Not met	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). However, domain removal is inherent to the truncating mechanism already captured by PVS1. A cancerhotspots.org statistically significant hotspot was not identified at this residue. Applying PM1 on top of PVS1 for the same truncation would constitute double-counting of the same underlying evidence.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per instruction.
PM4	N/A	PM4 applies to non-null protein length-altering variants (in-frame deletions/insertions, stop-loss). This variant is a nonsense change producing a premature termination codon; the null effect is assessed under PVS1, not PM4.
PM5	Not met	No ClinVar-listed pathogenic missense variant at the same residue (Gln53) was identified. The PM5 candidate search was unable to harvest comparator variants for a nonsense change at this position. The variant is absent from ClinVar entirely.	pm5_candidates clinvar
PM6	Not met	No confirmed de novo observation was identified for this variant in any publication or clinical database.
PP1	Not met	No segregation data are available for this variant. No family studies or co-segregation reports were identified.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense change, not a missense variant.
PP3	N/A	In silico predictors (REVEL, BayesDel) are not applicable to non-SNV variants and returned null scores. SpliceAI predicts no splice impact (max delta score 0.01). The pathogenic mechanism of this nonsense variant is established by the variant type alone (PVS1); stacking PP3 for in silico evidence on a null variant is not appropriate under the PMC6185798 framework.	spliceai
PP4	Not met	No patient phenotype data are available for this variant. The variant is absent from ClinVar with no associated clinical assertions or phenotype information.	clinvar
PP5	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as pathogenic. PP5 requires a reputable source to have classified the variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. The allele frequency of 0.0 does not meet the BA1 threshold (>1%).	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. The allele frequency of 0.0 does not meet the BS1 threshold (>0.3%).	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adult individuals. The variant is absent from population databases and has no reported carriers.
BS3	Not met	No functional studies demonstrating no damaging effect have been identified for this variant. OncoKB lists this variant as Unknown Oncogenic Effect, with no benign functional evidence.	oncokb
BS4	Not met	No segregation data are available for this variant. No families have been studied to assess lack of co-segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) variant, not a missense variant.
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant. No phase information is available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This variant is a frameshift-inducing deletion-insertion producing a premature stop codon, not an in-frame variant.
BP4	N/A	BP4 relies on multiple lines of computational evidence suggesting no impact. REVEL and BayesDel are not applicable to non-SNV variants. SpliceAI predicts no splice impact (max delta 0.01), but in silico benign prediction for a null variant is not clinically informative and would conflict with PVS1.	spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in any reported case carrying this variant. The variant has no associated clinical data.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign. BP6 requires a reputable source to have classified the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an indel producing a premature termination codon (nonsense change), not a synonymous variant.

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