chr7-116778957-T-G

Position:

• chr7-116778957-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000245.4(MET):​c.3522T>G​(p.His1174Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MET NM_000245.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001303
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3331651).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3522T>G	p.His1174Gln	missense_variant, splice_region_variant	17/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3576T>G	p.His1192Gln	missense_variant, splice_region_variant	17/21		NP_001120972.1
MET	NM_001324402.2	c.2232T>G	p.His744Gln	missense_variant, splice_region_variant	16/20		NP_001311331.1
MET	XM_011516223.2	c.3579T>G	p.His1193Gln	missense_variant, splice_region_variant	18/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3522T>G	p.His1174Gln	missense_variant, splice_region_variant	17/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3576T>G	p.His1192Gln	missense_variant, splice_region_variant	17/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1127T>G		splice_region_variant, non_coding_transcript_exon_variant	16/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1127T>G		3_prime_UTR_variant	16/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248840 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134974

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461338 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.0047	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.76	N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;P
Vest4		0.64
MutPred		0.43		Gain of ubiquitination at K1179 (P = 0.071);.;
MVP		0.79
MPC		1.9
ClinPred		0.46	T
GERP RS		-5.8
Varity_R		0.56
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.16
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

Publications

LitVar

Other links and lift over

dbSNP: rs146651797; hg19: chr7-116419011;