rs183642

Variant names:

• chr7-116793576-G-A
• rs183642
• NM_000245.4:c.3799-2079G>A

Variant summary

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

The NM_000245.4(MET):​c.3799-2079G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 151,788 control chromosomes in the GnomAD database, including 11,126 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 (11126 hom., cov: 30)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.480
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3799-2079G>A		intron_variant	Intron 19 of 20	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3853-2079G>A		intron_variant	Intron 19 of 20		NP_001120972.1
MET	NM_001324402.2	c.2509-2079G>A		intron_variant	Intron 18 of 19		NP_001311331.1
MET	XM_011516223.2	c.3856-2079G>A		intron_variant	Intron 20 of 21		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3799-2079G>A		intron_variant	Intron 19 of 20	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3853-2079G>A		intron_variant	Intron 19 of 20	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1404-2079G>A		intron_variant	Intron 18 of 19	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52997 AN: 151668 Hom.: 11139 Cov.: 30

Gnomad AFR AF: 0.0957

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.349 AC: 52968 AN: 151788 Hom.: 11126 Cov.: 30 AF XY: 0.352 AC XY: 26090 AN XY: 74150

African (AFR) AF: 0.0954 AC: 3952 AN: 41404

American (AMR) AF: 0.446 AC: 6810 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1690 AN: 3464

East Asian (EAS) AF: 0.471 AC: 2418 AN: 5132

South Asian (SAS) AF: 0.457 AC: 2199 AN: 4812

European-Finnish (FIN) AF: 0.383 AC: 4023 AN: 10494

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

European-Non Finnish (NFE) AF: 0.451 AC: 30661 AN: 67910

Other (OTH) AF: 0.387 AC: 814 AN: 2106

Alfa AF: 0.427 Hom.: 7379

Bravo AF: 0.344

Asia WGS AF: 0.415 AC: 1441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.77
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs183642; hg19: chr7-116433630;