7-116785439-G-A

Variant names:

• chr7-116785439-G-A
• rs10435378
• NM_000245.4:c.3798+1970G>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.3798+1970G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 152,012 control chromosomes in the GnomAD database, including 33,728 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 (33728 hom., cov: 31)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.924
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 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.3798+1970G>A		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.3852+1970G>A		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.2508+1970G>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.3798+1970G>A		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.3852+1970G>A		intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.*1403+1970G>A		intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98376 AN: 151894 Hom.: 33655 Cov.: 31

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.606

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

GnomAD4 genome AF: 0.648 AC: 98522 AN: 152012 Hom.: 33728 Cov.: 31 AF XY: 0.645 AC XY: 47951 AN XY: 74288

African (AFR) AF: 0.896 AC: 37151 AN: 41486

American (AMR) AF: 0.553 AC: 8454 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1779 AN: 3466

East Asian (EAS) AF: 0.522 AC: 2687 AN: 5150

South Asian (SAS) AF: 0.540 AC: 2594 AN: 4806

European-Finnish (FIN) AF: 0.618 AC: 6518 AN: 10552

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37244 AN: 67944

Other (OTH) AF: 0.611 AC: 1290 AN: 2110

Alfa AF: 0.618 Hom.: 4431

Bravo AF: 0.653

Asia WGS AF: 0.575 AC: 2000 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.78
DANN	Benign	0.37
PhyloP100		-0.92
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: rs10435378; hg19: chr7-116425493;