7-116763206-T-G

Position:

• chr7-116763206-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000245.4(MET):​c.2521T>G​(p.Phe841Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-116763206-T-G is Pathogenic according to our data. Variant chr7-116763206-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 183686.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-116763206-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.2521T>G	p.Phe841Val	missense_variant	11/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.2521T>G	p.Phe841Val	missense_variant	11/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.2575T>G	p.Phe859Val	missense_variant	11/21	1		A2
MET	ENST00000436117.3	c.*126T>G		3_prime_UTR_variant, NMD_transcript_variant	10/20	1
MET	ENST00000422097.2	c.2521T>G	p.Phe841Val	missense_variant	11/12	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 97 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2015

- -

Nonsyndromic Hearing Loss and Deafness, Autosomal Recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

research

School of Biological Sciences, University of the Punjab

Mar 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.81	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.87	N;N;D
REVEL	Uncertain	0.49
Sift	Benign	0.087	T;T;T
Sift4G	Benign	0.51	T;T;D
Polyphen		0.064	B;B;.
Vest4		0.87
MutPred		0.32		Gain of sheet (P = 0.039);.;.;
MVP		0.80
MPC		1.0
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.93

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

Other links and lift over

dbSNP: rs794728016; hg19: chr7-116403260;