7-116759452-G-C

Variant names:

• chr7-116759452-G-C
• rs771976817
• NM_000245.4:c.2326G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_000245.4(MET):​c.2326G>C​(p.Val776Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V776D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.92
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20619738).
• BP6: Variant 7-116759452-G-C is Benign according to our data. Variant chr7-116759452-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 524852.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000411 (6/1461486) while in subpopulation AMR AF = 0.000134 (6/44676). AF 95% confidence interval is 0.0000581. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.2326G>C	p.Val776Leu	missense	Exon 10 of 21	NP_000236.2
	MET	NM_001127500.3		c.2380G>C	p.Val794Leu	missense	Exon 10 of 21	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.1036G>C	p.Val346Leu	missense	Exon 9 of 20	NP_001311331.1	B4DLF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.2326G>C	p.Val776Leu	missense	Exon 10 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.2380G>C	p.Val794Leu	missense	Exon 10 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.2264+832G>C		intron	N/A	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248876 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461486 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.000134 AC: 6 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111828

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.17	B
Vest4		0.24
MutPred		0.46		Gain of sheet (P = 0.1208)
MVP		0.57
MPC		0.30
ClinPred		0.10	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.81
Mutation Taster		=76/24	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: rs771976817; hg19: chr7-116399506;