rs17526983

Variant names:

• chr7-116776369-G-A
• rs17526983
• NM_000245.4:c.3260-1020G>A

Variant summary

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

The NM_000245.4(MET):​c.3260-1020G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 152,198 control chromosomes in the GnomAD database, including 120 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 0.035 (120 hom., cov: 33)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.3260-1020G>A		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.3314-1020G>A		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.1970-1020G>A		intron	N/A	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.3260-1020G>A		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.3314-1020G>A		intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.*865-1020G>A		intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5322 AN: 152080 Hom.: 120 Cov.: 33

Gnomad AFR AF: 0.00901

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0431

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

GnomAD4 genome AF: 0.0350 AC: 5320 AN: 152198 Hom.: 120 Cov.: 33 AF XY: 0.0333 AC XY: 2477 AN XY: 74414

African (AFR) AF: 0.00896 AC: 372 AN: 41516

American (AMR) AF: 0.0325 AC: 497 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4828

European-Finnish (FIN) AF: 0.0439 AC: 465 AN: 10598

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0542 AC: 3684 AN: 68000

Other (OTH) AF: 0.0427 AC: 90 AN: 2108

Alfa AF: 0.0410 Hom.: 119

Bravo AF: 0.0329

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.44
DANN	Benign	0.48
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism

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: rs17526983; hg19: chr7-116416423;