7-81734871-C-T

Variant names:

• chr7-81734871-C-T
• rs12540393
• NM_000601.6:c.866-5092G>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.866-5092G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 152,006 control chromosomes in the GnomAD database, including 45,435 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 0.77 (45435 hom., cov: 31)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.866-5092G>A		intron_variant	Intron 7 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.851-5092G>A		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.866-5092G>A		intron_variant	Intron 7 of 17	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7	c.851-5092G>A		intron_variant	Intron 7 of 17	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1	n.117+34343C>T		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1	n.172-2110C>T		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117192 AN: 151888 Hom.: 45405 Cov.: 31

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.867

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.865

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.808

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

GnomAD4 genome AF: 0.772 AC: 117273 AN: 152006 Hom.: 45435 Cov.: 31 AF XY: 0.772 AC XY: 57372 AN XY: 74302

African (AFR) AF: 0.748 AC: 31037 AN: 41486

American (AMR) AF: 0.831 AC: 12681 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 3008 AN: 3470

East Asian (EAS) AF: 0.840 AC: 4308 AN: 5128

South Asian (SAS) AF: 0.865 AC: 4178 AN: 4830

European-Finnish (FIN) AF: 0.725 AC: 7671 AN: 10582

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

European-Non Finnish (NFE) AF: 0.763 AC: 51859 AN: 67948

Other (OTH) AF: 0.809 AC: 1703 AN: 2106

Alfa AF: 0.768 Hom.: 177769

Bravo AF: 0.777

Asia WGS AF: 0.838 AC: 2916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.82
DANN	Benign	0.50
PhyloP100		-1.3
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: rs12540393; hg19: chr7-81364187;