rs35776110

Variant names:

• chr7-116700043-C-T
• rs35776110
• NM_000245.4:c.959C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-116700043-C-T
• chr7-116700043-C-A
• chr7-116700043-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP3 BP4_Moderate BP6_Very_Strong BS1

The NM_000245.4(MET):​c.959C>T​(p.Ala320Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,886 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A320T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.57
• Publications: 13 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]

COMETT (HGNC:51196): (cytosolic oncogenic antisense to MET transcript) This gene encodes a natural antisense transcript highly expressed in papillary thyroid carcinomas harboring BRAF V600E mutation or RET gene rearrangements. This lncRNA induces the downstream MAPK pathway and is part of a co-expression network including different oncogenes belonging to the MAPK and PI3H/AKT pathways. In thyroid carcinomas, this gene has oncogenic properties associated with increased proliferation and drug resistance. [provided by RefSeq, Jan 2020]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.16254735).
• BP6: Variant 7-116700043-C-T is Benign according to our data. Variant chr7-116700043-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000427 (65/152276) while in subpopulation AFR AF = 0.000938 (39/41558). AF 95% confidence interval is 0.000705. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.959C>T	p.Ala320Val	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.959C>T	p.Ala320Val	missense	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.959C>T	p.Ala320Val	missense	Exon 2 of 12	NP_001311330.1	E6Y365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.959C>T	p.Ala320Val	missense	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.959C>T	p.Ala320Val	missense	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.959C>T		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000289 AC: 72 AN: 248846 AF XY: 0.000252

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461610 Hom.: 0 Cov.: 32 AF XY: 0.000177 AC XY: 129 AN XY: 727118

African (AFR) AF: 0.000837 AC: 28 AN: 33436

American (AMR) AF: 0.000157 AC: 7 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86230

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000166 AC: 185 AN: 1111914

Other (OTH) AF: 0.000298 AC: 18 AN: 60380

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74462

African (AFR) AF: 0.000938 AC: 39 AN: 41558

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000369 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.00133 AC: 5

ESP6500EA AF: 0.000489 AC: 4

ExAC AF: 0.000373 AC: 45

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Papillary renal cell carcinoma type 1 (2)
-	-	2	Renal cell carcinoma (2)
-	-	1	Intellectual disability (1)
-	-	1	MET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.64
MPC		0.89
ClinPred		0.12	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.77
Mutation Taster		=26/74	disease causing

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: rs35776110; hg19: chr7-116340097; COSMIC: COSV59259939; COSMIC: COSV59259939;