rs374050750

Variant names:

• chr7-116699226-G-A
• rs374050750
• NM_000245.4:c.142G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116699226-G-A
• chr7-116699226-G-C
• chr7-116699226-G-T

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.142G>A​(p.Ala48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,944 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A48V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 2.13
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090656936).
• BP6: Variant 7-116699226-G-A is Benign according to our data. Variant chr7-116699226-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 454188.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000176 (257/1461720) while in subpopulation NFE AF = 0.000219 (243/1111908). AF 95% confidence interval is 0.000195. There are 0 homozygotes in GnomAdExome4. There are 118 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_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.142G>A	p.Ala48Thr	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.142G>A	p.Ala48Thr	missense	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.142G>A	p.Ala48Thr	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.142G>A	p.Ala48Thr	missense	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.142G>A	p.Ala48Thr	missense	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000456159.1	TSL:1	c.199G>A	p.Ala67Thr	missense	Exon 3 of 3	ENSP00000413857.1	C9JKM5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000682 AC: 17 AN: 249380 AF XY: 0.0000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.000162 AC XY: 118 AN XY: 727156

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000671 AC: 3 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000219 AC: 243 AN: 1111908

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74428

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

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

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 97 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	MET-related disorder (1)
-	-	1	Papillary renal cell carcinoma type 1 (1)
-	1	-	Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia (1)
-	1	-	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.054
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.29	B
Vest4		0.12
MVP		0.30
MPC		0.54
ClinPred		0.062	T
GERP RS		5.0
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.22
gMVP		0.68
Mutation Taster		=86/14	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: rs374050750; hg19: chr7-116339280;