rs766929091

Variant names:

• chr7-116731758-A-G
• rs766929091
• NM_000245.4:c.1291A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-116731758-A-G
• chr7-116731758-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PVS1_Supporting BP6 BS1

The NM_001324402.2(MET):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MET NM_001324402.2 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.75
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 33 codons. Genomic position: 116731854. Lost 0.034 part of the original CDS.
• BP6: Variant 7-116731758-A-G is Benign according to our data. Variant chr7-116731758-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572844.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000821 (12/1461812) while in subpopulation SAS AF = 0.000128 (11/86256). AF 95% confidence interval is 0.0000712. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324402.2. 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.1291A>G	p.Met431Val	missense	Exon 3 of 21	NP_000236.2
	MET	NM_001324402.2		c.1A>G	p.Met1?	start_lost	Exon 2 of 20	NP_001311331.1	B4DLF5
	MET	NM_001127500.3		c.1291A>G	p.Met431Val	missense	Exon 3 of 21	NP_001120972.1	P08581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.1291A>G	p.Met431Val	missense	Exon 3 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.1291A>G	p.Met431Val	missense	Exon 3 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.1291A>G		non_coding_transcript_exon	Exon 3 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 249462 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000821 AC: 12 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000662 AC: 8

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Arthrogryposis, distal, IIa 11 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	MET-related disorder (1)
-	1	-	not provided (1)
-	1	-	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.44
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.54	T
Sift4G	Benign	0.24	T
Polyphen		0.030	B
Vest4		0.55
MutPred		0.64		Loss of catalytic residue at V427 (P = 0.0331)
MVP		0.64
MPC		0.26
ClinPred		0.038	T
GERP RS		1.9
Varity_R		0.24
gMVP		0.55
Mutation Taster		=85/15	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: rs766929091; hg19: chr7-116371812;