rs33917957

Variant names:

• chr7-116700208-A-G
• rs33917957
• NM_000245.4:c.1124A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-116700208-A-G
• chr7-116700208-A-C
• chr7-116700208-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000245.4(MET):​c.1124A>G​(p.Asn375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,594,672 control chromosomes in the GnomAD database, including 630 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. N375K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (48 hom., cov: 33)
  • Exomes 𝑓: 0.022 (582 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 2.92
• Publications: 104 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023828745).
• BP6: Variant 7-116700208-A-G is Benign according to our data. Variant chr7-116700208-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0658 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.1124A>G	p.Asn375Ser	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.1124A>G	p.Asn375Ser	missense	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.1124A>G	p.Asn375Ser	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.1124A>G	p.Asn375Ser	missense	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.1124A>G	p.Asn375Ser	missense	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.1124A>G		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2953 AN: 152194 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.0724

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0270 AC: 6190 AN: 228932 AF XY: 0.0294

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.0668

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0223 AC: 32104 AN: 1442360 Hom.: 582 Cov.: 32 AF XY: 0.0237 AC XY: 16953 AN XY: 716604

African (AFR) AF: 0.00510 AC: 165 AN: 32356

American (AMR) AF: 0.00641 AC: 256 AN: 39952

Ashkenazi Jewish (ASJ) AF: 0.00329 AC: 82 AN: 24914

East Asian (EAS) AF: 0.0508 AC: 2013 AN: 39606

South Asian (SAS) AF: 0.0693 AC: 5648 AN: 81504

European-Finnish (FIN) AF: 0.0402 AC: 2127 AN: 52854

Middle Eastern (MID) AF: 0.0101 AC: 57 AN: 5638

European-Non Finnish (NFE) AF: 0.0185 AC: 20426 AN: 1106002

Other (OTH) AF: 0.0223 AC: 1330 AN: 59534

GnomAD4 genome AF: 0.0194 AC: 2949 AN: 152312 Hom.: 48 Cov.: 33 AF XY: 0.0212 AC XY: 1577 AN XY: 74472

African (AFR) AF: 0.00697 AC: 290 AN: 41580

American (AMR) AF: 0.00870 AC: 133 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0621 AC: 322 AN: 5184

South Asian (SAS) AF: 0.0721 AC: 348 AN: 4828

European-Finnish (FIN) AF: 0.0446 AC: 474 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0192 AC: 1308 AN: 68022

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0188 Hom.: 142

Bravo AF: 0.0145

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00675 AC: 26

ESP6500EA AF: 0.0182 AC: 151

ExAC AF: 0.0278 AC: 3356

Asia WGS AF: 0.0700 AC: 244 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	6	not provided (6)
-	-	4	Papillary renal cell carcinoma type 1 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.15
Sift	Benign	0.096	T
Sift4G	Benign	0.21	T
Polyphen		0.043	B
Vest4		0.11
MPC		0.37
ClinPred		0.010	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.41
Mutation Taster		=90/10	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: rs33917957; hg19: chr7-116340262; COSMIC: COSV59260365; COSMIC: COSV59260365;