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METc.156_157delinsTTLikely pathogenic
Print report
Variant interpretation report

MET c.156_157delinsTT, p.(Gln53Ter)

NM_001127500.3:c.156_157delinsTT NP_001120972.1:p.(Gln53Ter) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MET

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
PVS1Very strong
PVS1 · very strong

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.

PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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 · 19 not met · 0 not assessed · 8 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_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).

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Gln53Ter at codon 53 of 1409 — early truncation with expected NMD
  • MET loss of function is an established germline disease mechanism for osteofibrous dysplasia
  • ClinGen SVI PVS1 framework (PMC6185798) supports PVS1 for nonsense variants in LOF-intolerant genes
Still missing
  • NM_001127500.3 is not MANE select or RefSeq select
  • confirm transcript relevance for the clinical indication
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AF = 0.0)
  • Absent from gnomAD v4.1 (AF = 0.0)
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 19 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no alternative nucleotide changes reported at the same codon
Sources
clinvar ↗
PS2 No de novo occurrence data are available for this variant. No publications or clinical reports documenting a confirmed de novo observation were identified. Details ▾Hide ▴
Still missing
  • No parental testing or de novo confirmation data available
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect — no functional data curated
Still missing
  • No functional studies available for this variant or systematically characterized range including codon 53
Sources
oncokb ↗
PS4 No case-control studies or enriched cohort data are available for this variant. The variant is absent from ClinVar with no affected individuals reported. Details ▾Hide ▴
Still missing
  • No case-control or cohort enrichment data available
Sources
clinvar ↗
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). 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. Details ▾Hide ▴
Evidence considered
  • No statistically significant hotspot at codon 53 per cancerhotspots.org
  • Domain loss is inherent to the truncating mechanism already assessed under PVS1
PM5 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. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense comparator identified at codon 53
  • Variant absent from ClinVar
  • no same-residue pathogenic variants available
Sources
pm5_candidatesclinvar ↗
PM6 No confirmed de novo observation was identified for this variant in any publication or clinical database. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No segregation data are available for this variant. No family studies or co-segregation reports were identified. Details ▾Hide ▴
Still missing
  • No segregation data available
PP4 No patient phenotype data are available for this variant. The variant is absent from ClinVar with no associated clinical assertions or phenotype information. Details ▾Hide ▴
Still missing
  • No patient phenotype data available
Sources
clinvar ↗
PP5 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar — no classification available
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1. The allele frequency of 0.0 does not meet the BA1 threshold (>1%). Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency = 0.0 — below BA1 threshold of 1%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD. The allele frequency of 0.0 does not meet the BS1 threshold (>0.3%). Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency = 0.0 — below BS1 threshold of 0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Still missing
  • No observation data in healthy adults
BS3 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. Details ▾Hide ▴
Still missing
  • No functional studies showing benign effect
Sources
oncokb ↗
BS4 No segregation data are available for this variant. No families have been studied to assess lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant. No phase information is available. Details ▾Hide ▴
Still missing
  • No phase data or trans configuration data available
BP5 No alternative molecular basis for disease has been identified in any reported case carrying this variant. The variant has no associated clinical data. Details ▾Hide ▴
Still missing
  • No clinical case data available
BP6 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar — no classification available
Sources
clinvar ↗
PS5 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. Details ▾Hide ▴
Still missing
  • No functional data available
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ASkipped per instruction. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a nonsense change, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AIn 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score 0.01 — no predicted splice impact
  • REVEL and BayesDel not applicable to indel variants
Sources
spliceai ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 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. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.01 — no splice impact predicted
Sources
spliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
MET
Transcript
NM_001127500.3
Coding (HGVS c.)
NM_001127500.3:c.156_157delinsTT
Protein (HGVS p.)
NP_001120972.1:p.(Gln53Ter)
GRCh38
chr7:116699240 CC>TT
GRCh37
chr7:116339294 CC>TT

Gene diagram

Every interpreted variant in MET, mapped onto the exon structure of NM_001127500.3. Select a row to find it on the plot.

METNM_001127500.3
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 -169 bp
0.000
SpliceAI acceptor gainat +74 bp
0.010
SpliceAI donor lossat +372 bp
0.000
SpliceAI donor gainat -48 bp
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AIn 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score 0.01 — no predicted splice impact
  • REVEL and BayesDel not applicable to indel variants
Sources
spliceai ↗
BP4 N/ABP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta 0.01 — no splice impact predicted
Sources
spliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 0.010 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 = 0.01).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.