7-116700264-C-A

Position:

• chr7-116700264-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000245.4(MET):​c.1180C>A​(p.His394Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,198 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H394H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.49

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13562238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.1180C>A	p.His394Asn	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.1180C>A	p.His394Asn	missense_variant	2/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.1180C>A	p.His394Asn	missense_variant	2/21	1		A2
MET	ENST00000436117.3	c.1180C>A	p.His394Asn	missense_variant, NMD_transcript_variant	2/20	1
MET	ENST00000422097.2	c.1180C>A	p.His394Asn	missense_variant	2/12	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451198 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MET-related disease. ClinVar contains an entry for this variant (Variation ID: 41612). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with asparagine at codon 394 of the MET protein (p.His394Asn). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and asparagine. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jul 13, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	0.013
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.68	N;N;N
MutationTaster	Benign	0.67	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.82	P;B;.
Vest4		0.29
MutPred		0.48		Loss of catalytic residue at H394 (P = 0.005);Loss of catalytic residue at H394 (P = 0.005);Loss of catalytic residue at H394 (P = 0.005);
MVP		0.46
MPC		0.68
ClinPred		0.29	T
GERP RS		6.0
Varity_R		0.15
gMVP		0.70

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

Other links and lift over

dbSNP: rs201628326; hg19: chr7-116340318;