rs2283053

Variant names:

• chr7-116786965-A-G
• rs2283053
• NM_000245.4:c.3798+3496A>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.3798+3496A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,186 control chromosomes in the GnomAD database, including 2,006 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 0.15 (2006 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.300
• 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: 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3798+3496A>G		intron_variant	Intron 19 of 20	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3852+3496A>G		intron_variant	Intron 19 of 20		NP_001120972.1
MET	NM_001324402.2	c.2508+3496A>G		intron_variant	Intron 18 of 19		NP_001311331.1
MET	XM_011516223.2	c.3855+3496A>G		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.3798+3496A>G		intron_variant	Intron 19 of 20	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3852+3496A>G		intron_variant	Intron 19 of 20	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1403+3496A>G		intron_variant	Intron 18 of 19	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22098 AN: 152068 Hom.: 2008 Cov.: 32

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.145 AC: 22095 AN: 152186 Hom.: 2006 Cov.: 32 AF XY: 0.147 AC XY: 10924 AN XY: 74402

African (AFR) AF: 0.0408 AC: 1695 AN: 41554

American (AMR) AF: 0.117 AC: 1782 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 704 AN: 3466

East Asian (EAS) AF: 0.284 AC: 1466 AN: 5166

South Asian (SAS) AF: 0.231 AC: 1115 AN: 4818

European-Finnish (FIN) AF: 0.193 AC: 2040 AN: 10578

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12642 AN: 67990

Other (OTH) AF: 0.144 AC: 305 AN: 2116

Alfa AF: 0.148 Hom.: 327

Bravo AF: 0.133

Asia WGS AF: 0.251 AC: 870 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.94
DANN	Benign	0.62
PhyloP100		-0.30
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: rs2283053; hg19: chr7-116427019;