chr7-81740948-G-T

Variant names:

• chr7-81740948-G-T
• rs9642131
• NM_000601.6:c.865+2405C>A

Variant summary

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

The NM_000601.6(HGF):​c.865+2405C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 152,040 control chromosomes in the GnomAD database, including 46,637 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 0.78 (46637 hom., cov: 31)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 6 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 = 0.843 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.865+2405C>A		intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.850+2405C>A		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.865+2405C>A		intron	N/A	ENSP00000222390.5
	HGF	ENST00000457544.7	TSL:1	c.850+2405C>A		intron	N/A	ENSP00000391238.2
	ENSG00000300407	ENST00000771413.1		n.118-39275G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118796 AN: 151924 Hom.: 46604 Cov.: 31

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.867

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.811

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

GnomAD4 genome AF: 0.782 AC: 118882 AN: 152040 Hom.: 46637 Cov.: 31 AF XY: 0.782 AC XY: 58131 AN XY: 74316

African (AFR) AF: 0.784 AC: 32534 AN: 41480

American (AMR) AF: 0.834 AC: 12751 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 3005 AN: 3466

East Asian (EAS) AF: 0.839 AC: 4333 AN: 5162

South Asian (SAS) AF: 0.865 AC: 4173 AN: 4822

European-Finnish (FIN) AF: 0.726 AC: 7668 AN: 10556

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51873 AN: 67956

Other (OTH) AF: 0.812 AC: 1717 AN: 2114

Alfa AF: 0.776 Hom.: 6440

Bravo AF: 0.789

Asia WGS AF: 0.842 AC: 2927 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	10
DANN	Benign	0.77
PhyloP100		1.0
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: rs9642131; hg19: chr7-81370264;