NM_000601.6:c.866-4802A>C

Variant names:

• chr7-81734581-T-G
• rs4732404
• NM_000601.6:c.866-4802A>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.866-4802A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 151,966 control chromosomes in the GnomAD database, including 51,834 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 0.82 (51834 hom., cov: 31)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• Publications: 7 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 (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000601.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	NM_000601.6	MANE Select	c.866-4802A>C		intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.851-4802A>C		intron	N/A	NP_001010932.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	ENST00000222390.11	TSL:1 MANE Select	c.866-4802A>C		intron	N/A	ENSP00000222390.5
	HGF	ENST00000457544.7	TSL:1	c.851-4802A>C		intron	N/A	ENSP00000391238.2
	ENSG00000300407	ENST00000771413.1		n.117+34053T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124836 AN: 151846 Hom.: 51783 Cov.: 31

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.867

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.904

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.832

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

GnomAD4 genome AF: 0.822 AC: 124945 AN: 151966 Hom.: 51834 Cov.: 31 AF XY: 0.821 AC XY: 60989 AN XY: 74274

African (AFR) AF: 0.925 AC: 38373 AN: 41476

American (AMR) AF: 0.849 AC: 12939 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 3004 AN: 3466

East Asian (EAS) AF: 0.839 AC: 4324 AN: 5154

South Asian (SAS) AF: 0.866 AC: 4178 AN: 4826

European-Finnish (FIN) AF: 0.726 AC: 7662 AN: 10560

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51873 AN: 67926

Other (OTH) AF: 0.833 AC: 1759 AN: 2112

Alfa AF: 0.788 Hom.: 60887

Bravo AF: 0.835

Asia WGS AF: 0.850 AC: 2955 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.86
DANN	Benign	0.62
PhyloP100		-0.61
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: rs4732404; hg19: chr7-81363897;