rs2286194

Positions:

• chr7-81726133-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000601.6(HGF):​c.1041-116A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,035,140 control chromosomes in the GnomAD database, including 20,588 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2996 hom., cov: 32)
  • Exomes 𝑓: 0.20 (17592 hom.)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.284

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-81726133-T-A is Benign according to our data. Variant chr7-81726133-T-A is described in ClinVar as [Benign]. Clinvar id is 1261544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81726133-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGF	NM_000601.6	c.1041-116A>T		intron_variant		ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1026-116A>T		intron_variant			NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1041-116A>T		intron_variant		1	NM_000601.6	ENSP00000222390	P4
HGF	ENST00000457544.7	c.1026-116A>T		intron_variant		1		ENSP00000391238	A1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29636 AN: 152094 Hom.: 2994 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.197 AC: 174012 AN: 882928 Hom.: 17592 AF XY: 0.201 AC XY: 92673 AN XY: 460420

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.273

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.195 AC: 29651 AN: 152212 Hom.: 2996 Cov.: 32 AF XY: 0.194 AC XY: 14407 AN XY: 74426

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.208

Alfa AF: 0.198 Hom.: 375

Bravo AF: 0.196

Asia WGS AF: 0.223 AC: 778 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs2286194; hg19: chr7-81355449; COSMIC: COSV55958997;