chr7-116775051-C-A

Position:

chr7-116775051-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000245.4(MET):c.3199C>A(p.Gln1067Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MET
NM_000245.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.44

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=0.111367136).

BP6

Variant 7-116775051-C-A is Benign according to our data. Variant chr7-116775051-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MET	NM_000245.4 linkuse as main transcript	c.3199C>A	p.Gln1067Lys	missense_variant	15/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3 linkuse as main transcript	c.3253C>A	p.Gln1085Lys	missense_variant	15/21		NP_001120972.1
MET	NM_001324402.2 linkuse as main transcript	c.1909C>A	p.Gln637Lys	missense_variant	14/20		NP_001311331.1
MET	XM_011516223.2 linkuse as main transcript	c.3256C>A	p.Gln1086Lys	missense_variant	16/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8 linkuse as main transcript	c.3199C>A	p.Gln1067Lys	missense_variant	15/21	1	NM_000245.4	ENSP00000380860	P3	P08581-1
MET	ENST00000318493.11 linkuse as main transcript	c.3253C>A	p.Gln1085Lys	missense_variant	15/21	1		ENSP00000317272	A2	P08581-2
MET	ENST00000436117.3 linkuse as main transcript	c.*804C>A		3_prime_UTR_variant, NMD_transcript_variant	14/20	1		ENSP00000410980		P08581-3
MET	ENST00000454623.1 linkuse as main transcript	c.454C>A	p.Gln152Lys	missense_variant	3/3	5		ENSP00000398140

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249422

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000668

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000577

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2023	This alteration is classified as 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 20, 2021	- -

Autosomal recessive nonsyndromic hearing loss 97

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 05, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (Chan 2018); This variant is associated with the following publications: (PMID: 30093976) -

Renal cell carcinoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.33

T;.;.

Eigen

Benign

-0.074

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.38

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

1.7

N;N;D

REVEL

Benign

0.17

Sift

Benign

0.65

T;T;D

Sift4G

Benign

1.0

T;T;D

Polyphen

0.029

B;B;.

Vest4

0.43

MutPred

0.66

Gain of methylation at Q1067 (P = 0.0118);.;.;

MVP

0.71

MPC

0.33

ClinPred

0.076

GERP RS

5.6

Varity_R

0.79

gMVP

0.71

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