chr7-116798457-G-T

Variant names:

• chr7-116798457-G-T
• rs41741
• NM_000245.4:c.*2333G>T

Variant summary

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

The NM_000245.4(MET):​c.*2333G>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 174,520 control chromosomes in the GnomAD database, including 37,682 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 0.64 (31915 hom., cov: 32)
  • Exomes 𝑓: 0.71 (5767 hom.)
• Consequence: MET NM_000245.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180
• Publications: 20 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.*2333G>T		downstream_gene_variant		ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.*2333G>T		downstream_gene_variant			NP_001120972.1
MET	NM_001324402.2	c.*2333G>T		downstream_gene_variant			NP_001311331.1
MET	XM_011516223.2	c.*2333G>T		downstream_gene_variant			XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.*2333G>T		downstream_gene_variant		1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.*2333G>T		downstream_gene_variant		1		ENSP00000317272.6
MET	ENST00000436117.3	n.*4111G>T		downstream_gene_variant		1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97789 AN: 151930 Hom.: 31908 Cov.: 32

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.646

GnomAD4 exome AF: 0.710 AC: 15961 AN: 22472 Hom.: 5767 AF XY: 0.715 AC XY: 7419 AN XY: 10376

African (AFR) AF: 0.553 AC: 376 AN: 680

American (AMR) AF: 0.702 AC: 320 AN: 456

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 995 AN: 1398

East Asian (EAS) AF: 0.866 AC: 4155 AN: 4796

South Asian (SAS) AF: 0.824 AC: 155 AN: 188

European-Finnish (FIN) AF: 0.657 AC: 159 AN: 242

Middle Eastern (MID) AF: 0.644 AC: 94 AN: 146

European-Non Finnish (NFE) AF: 0.667 AC: 8539 AN: 12806

Other (OTH) AF: 0.664 AC: 1168 AN: 1760

GnomAD4 genome AF: 0.644 AC: 97846 AN: 152048 Hom.: 31915 Cov.: 32 AF XY: 0.646 AC XY: 48025 AN XY: 74320

African (AFR) AF: 0.544 AC: 22538 AN: 41468

American (AMR) AF: 0.674 AC: 10298 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2471 AN: 3466

East Asian (EAS) AF: 0.869 AC: 4505 AN: 5182

South Asian (SAS) AF: 0.801 AC: 3860 AN: 4816

European-Finnish (FIN) AF: 0.634 AC: 6687 AN: 10546

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45335 AN: 67976

Other (OTH) AF: 0.646 AC: 1361 AN: 2108

Alfa AF: 0.660 Hom.: 22339

Bravo AF: 0.640

Asia WGS AF: 0.820 AC: 2850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	11
DANN	Benign	0.53
PhyloP100		0.18
Mutation Taster		=94/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41741; hg19: chr7-116438511;