rs193688

Variant names:

• chr7-116793473-T-C
• rs193688
• NM_000245.4:c.3799-2182T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-116793473-T-C
• chr7-116793473-T-G

Variant summary

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

The NM_000245.4(MET):​c.3799-2182T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 151,620 control chromosomes in the GnomAD database, including 11,141 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 (11141 hom., cov: 30)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3799-2182T>C		intron_variant	Intron 19 of 20	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3853-2182T>C		intron_variant	Intron 19 of 20		NP_001120972.1
MET	NM_001324402.2	c.2509-2182T>C		intron_variant	Intron 18 of 19		NP_001311331.1
MET	XM_011516223.2	c.3856-2182T>C		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.3799-2182T>C		intron_variant	Intron 19 of 20	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3853-2182T>C		intron_variant	Intron 19 of 20	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1404-2182T>C		intron_variant	Intron 18 of 19	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53160 AN: 151504 Hom.: 11154 Cov.: 30

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.382

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: 0.350 AC: 53135 AN: 151620 Hom.: 11141 Cov.: 30 AF XY: 0.353 AC XY: 26135 AN XY: 74066

African (AFR) AF: 0.100 AC: 4146 AN: 41358

American (AMR) AF: 0.448 AC: 6823 AN: 15232

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

East Asian (EAS) AF: 0.472 AC: 2405 AN: 5092

South Asian (SAS) AF: 0.458 AC: 2186 AN: 4778

European-Finnish (FIN) AF: 0.382 AC: 4017 AN: 10502

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

European-Non Finnish (NFE) AF: 0.452 AC: 30649 AN: 67868

Other (OTH) AF: 0.387 AC: 819 AN: 2116

Alfa AF: 0.391 Hom.: 4512

Bravo AF: 0.345

Asia WGS AF: 0.415 AC: 1444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.42
PhyloP100		-1.1
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: rs193688; hg19: chr7-116433527;