7-81718232-T-G

Variant names:

• chr7-81718232-T-G
• rs5745718
• NM_000601.6:c.1272-867A>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.1272-867A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 152,166 control chromosomes in the GnomAD database, including 51,057 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 0.82 (51057 hom., cov: 33)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1272-867A>C		intron_variant	Intron 10 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1257-867A>C		intron_variant	Intron 10 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1272-867A>C		intron_variant	Intron 10 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124438 AN: 152048 Hom.: 51007 Cov.: 33

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.824

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

GnomAD4 genome AF: 0.819 AC: 124548 AN: 152166 Hom.: 51057 Cov.: 33 AF XY: 0.819 AC XY: 60935 AN XY: 74386

African (AFR) AF: 0.839 AC: 34823 AN: 41508

American (AMR) AF: 0.855 AC: 13064 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 2996 AN: 3468

East Asian (EAS) AF: 0.857 AC: 4445 AN: 5186

South Asian (SAS) AF: 0.872 AC: 4205 AN: 4824

European-Finnish (FIN) AF: 0.780 AC: 8268 AN: 10596

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.795 AC: 54073 AN: 67980

Other (OTH) AF: 0.822 AC: 1738 AN: 2114

Alfa AF: 0.773 Hom.: 2677

Bravo AF: 0.824

Asia WGS AF: 0.852 AC: 2964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.71
DANN	Benign	0.67
PhyloP100		-0.32
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: rs5745718; hg19: chr7-81347548;