rs201687037

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_000245.4(MET):c.901A>G(p.Thr301Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000568 in 1,614,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. T301T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 5.63

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10883194).

BP6

Variant 7-116699985-A-G is Benign according to our data. Variant chr7-116699985-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167292.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}. Variant chr7-116699985-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000355 (54/152296) while in subpopulation NFE AF= 0.000647 (44/68024). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4 linkuse as main transcript	c.901A>G	p.Thr301Ala	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.901A>G	p.Thr301Ala	missense_variant	2/21	1	NM_000245.4	P3	P08581-1
MET	ENST00000318493.11 linkuse as main transcript	c.901A>G	p.Thr301Ala	missense_variant	2/21	1		A2	P08581-2
MET	ENST00000436117.3 linkuse as main transcript	c.901A>G	p.Thr301Ala	missense_variant, NMD_transcript_variant	2/20	1			P08581-3
MET	ENST00000422097.2 linkuse as main transcript	c.901A>G	p.Thr301Ala	missense_variant	2/12	3

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000289

AC:

AN:

248896

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

135022

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.0000580

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:

0.000559

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000590

AC:

862

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000755

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000355

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00109

AC:

ESP6500EA

AF:

0.000489

AC:

ExAC

AF:

0.000215

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	The MET c.901A>G, p.Thr301Ala variant (rs201687037), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 167292). This variant is found in the general population with an overall allele frequency of 0.03% (81/280,300 alleles) in the Genome Aggregation Database. The threonine at codon 301 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.243). Based on the available information, the clinical significance of this variant is uncertain. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MET p.T301A variant was identified in one individual with colon cancer (Rohlin_2017_PMID: 27696107). The variant was identified in dbSNP (ID: rs201687037), ClinVar (classified as uncertain significance by EGL Genetic Diagnostics and Invitae; and as likely benign by Ambry Genetics), and COSMIC (lung, prostate, endometrium). The variant was identified in control databases in 81 of 280300 chromosomes at a frequency of 0.0002890, and was observed at the highest frequency in the European (non-Finnish) population in 71 of 128168 chromosomes (freq: 0.0005540) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T301 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict an impact on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27696107, 34882875) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Autosomal recessive nonsyndromic hearing loss 97

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 14, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Renal cell carcinoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2018

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

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.29

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.054

T;D;T

Sift4G

Benign

0.40

T;T;D

Polyphen

1.0

D;D;.

Vest4

0.69

MVP

0.44

MPC

0.88

ClinPred

0.053

GERP RS

6.2

Varity_R

0.39

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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