rs2286194

Variant names:

• chr7-81726133-T-A
• rs2286194
• NM_000601.6:c.1041-116A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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]

HGF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 39

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300407 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1261544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1041-116A>T		intron_variant	Intron 8 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1026-116A>T		intron_variant	Intron 8 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1041-116A>T		intron_variant	Intron 8 of 17	1	NM_000601.6	ENSP00000222390.5

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

African (AFR) AF: 0.208 AC: 4541 AN: 21826

American (AMR) AF: 0.207 AC: 8521 AN: 41132

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 6060 AN: 22206

East Asian (EAS) AF: 0.183 AC: 6584 AN: 35898

South Asian (SAS) AF: 0.273 AC: 19788 AN: 72464

European-Finnish (FIN) AF: 0.183 AC: 8591 AN: 47070

Middle Eastern (MID) AF: 0.281 AC: 1162 AN: 4136

European-Non Finnish (NFE) AF: 0.185 AC: 110439 AN: 596980

Other (OTH) AF: 0.202 AC: 8326 AN: 41216

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

African (AFR) AF: 0.202 AC: 8405 AN: 41536

American (AMR) AF: 0.191 AC: 2928 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 955 AN: 3468

East Asian (EAS) AF: 0.171 AC: 888 AN: 5182

South Asian (SAS) AF: 0.257 AC: 1239 AN: 4818

European-Finnish (FIN) AF: 0.175 AC: 1852 AN: 10600

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12809 AN: 67996

Other (OTH) AF: 0.208 AC: 439 AN: 2112

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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