7-116791952-T-C

Variant names:

• chr7-116791952-T-C
• rs193687
• NM_000245.4:c.3799-3703T>C

Variant summary

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

The NM_000245.4(MET):​c.3799-3703T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 152,368 control chromosomes in the GnomAD database, including 70,750 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 0.96 (70750 hom., cov: 34)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.98
• 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: 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 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.3799-3703T>C		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.3853-3703T>C		intron	N/A	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.2509-3703T>C		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.3799-3703T>C		intron	N/A	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.3853-3703T>C		intron	N/A	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.*1404-3703T>C		intron	N/A	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146680 AN: 152250 Hom.: 70705 Cov.: 34

Gnomad AFR AF: 0.990

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.960

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.958

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.969

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

GnomAD4 genome AF: 0.963 AC: 146784 AN: 152368 Hom.: 70750 Cov.: 34 AF XY: 0.963 AC XY: 71750 AN XY: 74508

African (AFR) AF: 0.990 AC: 41202 AN: 41598

American (AMR) AF: 0.959 AC: 14673 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 3371 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5183 AN: 5192

South Asian (SAS) AF: 0.957 AC: 4622 AN: 4830

European-Finnish (FIN) AF: 0.927 AC: 9832 AN: 10608

Middle Eastern (MID) AF: 0.956 AC: 281 AN: 294

European-Non Finnish (NFE) AF: 0.950 AC: 64656 AN: 68044

Other (OTH) AF: 0.970 AC: 2052 AN: 2116

Alfa AF: 0.952 Hom.: 8612

Bravo AF: 0.967

Asia WGS AF: 0.982 AC: 3413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.14
DANN	Benign	0.23
PhyloP100		-3.0
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: rs193687; hg19: chr7-116432006;