7-81733271-A-G

Variant names:

• chr7-81733271-A-G
• rs757832
• NM_000601.6:c.866-3492T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000601.6(HGF):​c.866-3492T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 151,654 control chromosomes in the GnomAD database, including 43,057 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43057 hom., cov: 32)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.866-3492T>C		intron_variant	Intron 7 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.851-3492T>C		intron_variant	Intron 7 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.866-3492T>C		intron_variant	Intron 7 of 17	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7	c.851-3492T>C		intron_variant	Intron 7 of 17	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1	n.117+32743A>G		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1	n.172-3710A>G		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.751 AC: 113879 AN: 151542 Hom.: 43028 Cov.: 32

Gnomad AFR AF: 0.744

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.876

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.789

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.751 AC: 113957 AN: 151654 Hom.: 43057 Cov.: 32 AF XY: 0.753 AC XY: 55776 AN XY: 74086

African (AFR) AF: 0.744 AC: 30855 AN: 41452

American (AMR) AF: 0.815 AC: 12394 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2869 AN: 3472

East Asian (EAS) AF: 0.840 AC: 4342 AN: 5168

South Asian (SAS) AF: 0.855 AC: 4125 AN: 4824

European-Finnish (FIN) AF: 0.695 AC: 7238 AN: 10412

Middle Eastern (MID) AF: 0.866 AC: 246 AN: 284

European-Non Finnish (NFE) AF: 0.733 AC: 49713 AN: 67814

Other (OTH) AF: 0.790 AC: 1665 AN: 2108

Alfa AF: 0.698 Hom.: 2219

Bravo AF: 0.774

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.65
PhyloP100		0.010
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: rs757832; hg19: chr7-81362587; COSMIC: COSV55950968;