7-116765333-T-C

Variant names:

• chr7-116765333-T-C
• rs2237717
• NM_000245.4:c.2583+2065T>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.2583+2065T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 149,660 control chromosomes in the GnomAD database, including 33,645 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 0.65 (33645 hom., cov: 25)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156
• Publications: 22 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.2583+2065T>C		intron_variant	Intron 11 of 20	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.2583+2065T>C		intron_variant	Intron 11 of 20	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.2637+2065T>C		intron_variant	Intron 11 of 20	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*188+2065T>C		intron_variant	Intron 10 of 19	1		ENSP00000410980.2
MET	ENST00000422097.2	c.2583+2065T>C		intron_variant	Intron 11 of 11	3		ENSP00000398776.2

Frequencies

GnomAD3 genomes AF: 0.651 AC: 97411 AN: 149562 Hom.: 33579 Cov.: 25

Gnomad AFR AF: 0.905

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.571

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.609

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

GnomAD4 genome AF: 0.652 AC: 97541 AN: 149660 Hom.: 33645 Cov.: 25 AF XY: 0.649 AC XY: 47239 AN XY: 72770

African (AFR) AF: 0.905 AC: 36693 AN: 40546

American (AMR) AF: 0.553 AC: 8293 AN: 14992

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1777 AN: 3462

East Asian (EAS) AF: 0.528 AC: 2660 AN: 5042

South Asian (SAS) AF: 0.542 AC: 2570 AN: 4738

European-Finnish (FIN) AF: 0.614 AC: 6105 AN: 9936

Middle Eastern (MID) AF: 0.590 AC: 171 AN: 290

European-Non Finnish (NFE) AF: 0.552 AC: 37378 AN: 67688

Other (OTH) AF: 0.615 AC: 1266 AN: 2060

Alfa AF: 0.592 Hom.: 57244

Bravo AF: 0.658

Asia WGS AF: 0.580 AC: 2018 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.2
DANN	Benign	0.73
PhyloP100		-0.16
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: rs2237717; hg19: chr7-116405387;