rs2074724

Variant names:

• chr7-81706949-C-T
• rs2074724
• NM_000601.6:c.1616+341G>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.1616+341G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 151,572 control chromosomes in the GnomAD database, including 55,425 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 0.85 (55425 hom., cov: 28)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.1616+341G>A		intron_variant	Intron 14 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.1601+341G>A		intron_variant	Intron 14 of 17		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.1616+341G>A		intron_variant	Intron 14 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129081 AN: 151454 Hom.: 55371 Cov.: 28

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.872

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.851

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

GnomAD4 genome AF: 0.852 AC: 129194 AN: 151572 Hom.: 55425 Cov.: 28 AF XY: 0.851 AC XY: 63022 AN XY: 74020

African (AFR) AF: 0.953 AC: 39493 AN: 41422

American (AMR) AF: 0.871 AC: 13202 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 3022 AN: 3464

East Asian (EAS) AF: 0.859 AC: 4377 AN: 5096

South Asian (SAS) AF: 0.871 AC: 4183 AN: 4802

European-Finnish (FIN) AF: 0.781 AC: 8213 AN: 10518

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.796 AC: 53982 AN: 67800

Other (OTH) AF: 0.850 AC: 1784 AN: 2100

Alfa AF: 0.831 Hom.: 6544

Bravo AF: 0.862

Asia WGS AF: 0.857 AC: 2976 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.23
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2074724; hg19: chr7-81336265;