rs587777950

Variant names:

• chr7-116741083-T-TC
• rs587777950
• NM_000245.4:c.1701+58_1701+59insC

Your query was ambiguous. Multiple possible variants found:

• chr7-116741083-T-TC
• chr7-116741083-T-TTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000245.4(MET):​c.1701+58_1701+59insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,326,394 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.863
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.1701+58_1701+59insC		intron_variant	Intron 5 of 20	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.1701+58_1701+59insC		intron_variant	Intron 5 of 20	1	NM_000245.4	ENSP00000380860.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.54e-7 AC: 1 AN: 1326394 Hom.: 0 Cov.: 27 AF XY: 0.00000151 AC XY: 1 AN XY: 662336

African (AFR) AF: 0.00 AC: 0 AN: 29212

American (AMR) AF: 0.00 AC: 0 AN: 38192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24660

East Asian (EAS) AF: 0.00 AC: 0 AN: 38206

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1008930

Other (OTH) AF: 0.00 AC: 0 AN: 55566

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.86

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

Other links and lift over

dbSNP: rs587777950; hg19: chr7-116381137;