rs141774517

Positions:

• chr7-81705679-C-A
• chr7-81705679-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000601.6(HGF):​c.1832G>T​(p.Ser611Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HGF NM_000601.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19

Genes affected

HGF (HGNC:4893): (hepatocyte growth factor) This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20953244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGF	NM_000601.6	c.1832G>T	p.Ser611Ile	missense_variant	16/18	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1817G>T	p.Ser606Ile	missense_variant	16/18		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1832G>T	p.Ser611Ile	missense_variant	16/18	1	NM_000601.6	ENSP00000222390	P4
HGF	ENST00000457544.7	c.1817G>T	p.Ser606Ile	missense_variant	16/18	1		ENSP00000391238	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460264 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.69	D;D;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.71	.;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-0.060	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.19
Sift	Benign	0.21	.;T;T
Sift4G	Benign	0.31	.;T;T
Polyphen		0.012	B;B;B
Vest4		0.33, 0.34
MutPred		0.47		Loss of glycosylation at S611 (P = 0.0471);Loss of glycosylation at S611 (P = 0.0471);.;
MVP		0.61
MPC		0.67
ClinPred		0.45	T
GERP RS		3.9
Varity_R		0.25
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs141774517; hg19: chr7-81334995; COSMIC: COSV99736942;