rs200074800

Variant names:

• chr7-116700123-G-A
• rs200074800
• NM_000245.4:c.1039G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116700123-G-A
• chr7-116700123-G-T
• chr7-116700123-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000245.4(MET):​c.1039G>A​(p.Ala347Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000949 in 1,605,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. A347V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (2 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10 O:1
• Conservation: PhyloP100: 6.38
• Publications: 14 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1481247).
• BP6: Variant 7-116700123-G-A is Benign according to our data. Variant chr7-116700123-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132694.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000676 (103/152306) while in subpopulation NFE AF = 0.00123 (84/68028). AF 95% confidence interval is 0.00102. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Unknown gene

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.1039G>A	p.Ala347Thr	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.1039G>A	p.Ala347Thr	missense	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.1039G>A	p.Ala347Thr	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.1039G>A	p.Ala347Thr	missense	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.1039G>A	p.Ala347Thr	missense	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.1039G>A		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000414 AC: 100 AN: 241642 AF XY: 0.000443

Gnomad AFR exome AF: 0.000261

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000823

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000977 AC: 1420 AN: 1452760 Hom.: 2 Cov.: 32 AF XY: 0.000974 AC XY: 703 AN XY: 721766

African (AFR) AF: 0.000242 AC: 8 AN: 33006

American (AMR) AF: 0.000115 AC: 5 AN: 43546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000592 AC: 5 AN: 84414

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53056

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.00122 AC: 1355 AN: 1107908

Other (OTH) AF: 0.000734 AC: 44 AN: 59928

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74470

African (AFR) AF: 0.000241 AC: 10 AN: 41574

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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: 10608

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

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000859 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00102 AC: 4

ESP6500EA AF: 0.00108 AC: 9

ExAC AF: 0.000447 AC: 54

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	2	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Papillary renal cell carcinoma type 1 (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 97 (1)
-	-	1	Hereditary cancer (1)
-	-	1	MET-related disorder (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.67
MVP		0.59
MPC		0.63
ClinPred		0.23	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.72
Mutation Taster		=14/86	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: rs200074800; hg19: chr7-116340177; COSMIC: COSV59266561; COSMIC: COSV59266561;