rs786204076

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_000245.4(MET):c.40C>T(p.Leu14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.561

Variant links:

Genes affected

MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]

MET links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.090137035).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000145 (22/152118) while in subpopulation AMR AF= 0.000917 (14/15270). AF 95% confidence interval is 0.000554. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4 linkuse as main transcript	c.40C>T	p.Leu14Phe	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.40C>T	p.Leu14Phe	missense_variant	2/21	1	NM_000245.4	P3	P08581-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000882

AC:

AN:

249328

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461642

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000145

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 97

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2023

- -

Renal cell carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 14 of the MET protein (p.Leu14Phe). This variant is present in population databases (rs763344951, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 188112). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MET protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a breast cancer patient (Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 35264596, 29641532) -

Papillary renal cell carcinoma type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.094

Eigen_PC

Benign

0.084

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.090

T;T;T;T

MetaSVM

Benign

-0.79

MutationTaster

Benign

0.82

D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.99

N;N;N;N

REVEL

Benign

0.065

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.0020, 0.0090

.;B;B;.

Vest4

0.093, 0.090, 0.13

MVP

0.42

MPC

0.28

ClinPred

0.026

GERP RS

4.1

Varity_R

0.072

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over