NM_000245.4:c.3799-4282C>T

Variant names:

• chr7-116791373-C-T
• rs193686
• NM_000245.4:c.3799-4282C>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.3799-4282C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 151,892 control chromosomes in the GnomAD database, including 36,154 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 0.69 (36154 hom., cov: 31)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 9 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.3799-4282C>T		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.3853-4282C>T		intron	N/A	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.2509-4282C>T		intron	N/A	NP_001311331.1	B4DLF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.3799-4282C>T		intron	N/A	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.3853-4282C>T		intron	N/A	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.*1404-4282C>T		intron	N/A	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104231 AN: 151774 Hom.: 36136 Cov.: 31

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.687 AC: 104302 AN: 151892 Hom.: 36154 Cov.: 31 AF XY: 0.692 AC XY: 51355 AN XY: 74206

African (AFR) AF: 0.619 AC: 25654 AN: 41456

American (AMR) AF: 0.737 AC: 11240 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2563 AN: 3472

East Asian (EAS) AF: 0.894 AC: 4593 AN: 5140

South Asian (SAS) AF: 0.831 AC: 4005 AN: 4818

European-Finnish (FIN) AF: 0.714 AC: 7505 AN: 10506

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46475 AN: 67940

Other (OTH) AF: 0.685 AC: 1443 AN: 2106

Alfa AF: 0.685 Hom.: 59317

Bravo AF: 0.682

Asia WGS AF: 0.857 AC: 2978 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.71
PhyloP100		-0.12
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: rs193686; hg19: chr7-116431427;