7-116798600-T-C

Variant names:

• chr7-116798600-T-C
• rs16945
• NM_000245.4:c.*2476T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000245.4(MET):​c.*2476T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,066 control chromosomes in the GnomAD database, including 11,166 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (11166 hom., cov: 32)
• Consequence: MET NM_000245.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• hereditary papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
• autosomal recessive nonsyndromic hearing loss 97

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteofibrous dysplasia

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis, distal, IIa 11

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.*2476T>C		downstream_gene_variant		ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.*2476T>C		downstream_gene_variant			NP_001120972.1
MET	NM_001324402.2	c.*2476T>C		downstream_gene_variant			NP_001311331.1
MET	XM_011516223.2	c.*2476T>C		downstream_gene_variant			XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.*2476T>C		downstream_gene_variant		1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.*2476T>C		downstream_gene_variant		1		ENSP00000317272.6
MET	ENST00000436117.3	n.*4254T>C		downstream_gene_variant		1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53413 AN: 151948 Hom.: 11179 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.393

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.351 AC: 53387 AN: 152066 Hom.: 11166 Cov.: 32 AF XY: 0.353 AC XY: 26254 AN XY: 74326

African (AFR) AF: 0.105 AC: 4360 AN: 41516

American (AMR) AF: 0.445 AC: 6797 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1690 AN: 3470

East Asian (EAS) AF: 0.470 AC: 2422 AN: 5150

South Asian (SAS) AF: 0.456 AC: 2194 AN: 4812

European-Finnish (FIN) AF: 0.382 AC: 4034 AN: 10560

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30669 AN: 67964

Other (OTH) AF: 0.388 AC: 820 AN: 2112

Alfa AF: 0.399 Hom.: 2172

Bravo AF: 0.346

Asia WGS AF: 0.415 AC: 1443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.29
PhyloP100		-0.14

Splicing

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

Other links and lift over

dbSNP: rs16945; hg19: chr7-116438654;