NM_000245.4:c.1125C>G

Variant names:

• chr7-116700209-C-G
• rs776693512
• NM_000245.4:c.1125C>G

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.1125C>G​(p.Asn375Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,441,852 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N375D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.826
• Publications: 3 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=0.11690968).
• BP6: Variant 7-116700209-C-G is Benign according to our data. Variant chr7-116700209-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 485743.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000025 (36/1441852) while in subpopulation EAS AF = 0.000909 (36/39606). AF 95% confidence interval is 0.000674. There are 1 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 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.1125C>G	p.Asn375Lys	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.1125C>G	p.Asn375Lys	missense	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.1125C>G	p.Asn375Lys	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.1125C>G	p.Asn375Lys	missense	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.1125C>G	p.Asn375Lys	missense	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.1125C>G		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000219 AC: 5 AN: 228090 AF XY: 0.0000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000250 AC: 36 AN: 1441852 Hom.: 1 Cov.: 32 AF XY: 0.0000195 AC XY: 14 AN XY: 716264

African (AFR) AF: 0.00 AC: 0 AN: 32360

American (AMR) AF: 0.00 AC: 0 AN: 39796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24894

East Asian (EAS) AF: 0.000909 AC: 36 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 81398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105846

Other (OTH) AF: 0.00 AC: 0 AN: 59520

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Papillary renal cell carcinoma type 1 (1)
-	1	-	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.1
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.82	L
PhyloP100		0.83
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.053
Sift	Benign	0.27	T
Sift4G	Benign	0.43	T
Polyphen		0.77	P
Vest4		0.32
MutPred		0.48		Gain of methylation at N375 (P = 0.0071)
MVP		0.34
MPC		0.50
ClinPred		0.039	T
GERP RS		1.3
Varity_R		0.22
gMVP		0.56
Mutation Taster		=38/62	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: rs776693512; hg19: chr7-116340263;