rs41735

Variant names:

• chr7-116795362-G-A
• rs41735
• NM_000245.4:c.3799-293G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116795362-G-A
• chr7-116795362-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000245.4(MET):​c.3799-293G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,036 control chromosomes in the GnomAD database, including 11,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (11144 hom., cov: 32)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00900
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 7-116795362-G-A is Benign according to our data. Variant chr7-116795362-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255261.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3799-293G>A		intron_variant	Intron 19 of 20	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3853-293G>A		intron_variant	Intron 19 of 20		NP_001120972.1
MET	NM_001324402.2	c.2509-293G>A		intron_variant	Intron 18 of 19		NP_001311331.1
MET	XM_011516223.2	c.3856-293G>A		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.3799-293G>A		intron_variant	Intron 19 of 20	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3853-293G>A		intron_variant	Intron 19 of 20	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1404-293G>A		intron_variant	Intron 18 of 19	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53051 AN: 151918 Hom.: 11157 Cov.: 32

Gnomad AFR AF: 0.0957

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.349 AC: 53022 AN: 152036 Hom.: 11144 Cov.: 32 AF XY: 0.351 AC XY: 26112 AN XY: 74294

African (AFR) AF: 0.0954 AC: 3959 AN: 41502

American (AMR) AF: 0.446 AC: 6813 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1689 AN: 3468

East Asian (EAS) AF: 0.470 AC: 2436 AN: 5178

South Asian (SAS) AF: 0.457 AC: 2200 AN: 4812

European-Finnish (FIN) AF: 0.383 AC: 4040 AN: 10544

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30670 AN: 67938

Other (OTH) AF: 0.386 AC: 814 AN: 2110

Alfa AF: 0.401 Hom.: 2278

Bravo AF: 0.344

Asia WGS AF: 0.413 AC: 1435 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.68
DANN	Benign	0.40
PhyloP100		0.0090
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: rs41735; hg19: chr7-116435416;