NM_000601.6:c.626-1418C>T

Variant names:

• chr7-81746538-G-A
• rs7804865
• NM_000601.6:c.626-1418C>T

Variant summary

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

The NM_000601.6(HGF):​c.626-1418C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,110 control chromosomes in the GnomAD database, including 50,034 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 0.81 (50034 hom., cov: 32)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328
• Publications: 2 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 = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.626-1418C>T		intron_variant	Intron 5 of 17	ENST00000222390.11	NP_000592.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11	c.626-1418C>T		intron_variant	Intron 5 of 17	1	NM_000601.6	ENSP00000222390.5

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122915 AN: 151992 Hom.: 49988 Cov.: 32

Gnomad AFR AF: 0.878

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.866

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.824

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

GnomAD4 genome AF: 0.809 AC: 123017 AN: 152110 Hom.: 50034 Cov.: 32 AF XY: 0.808 AC XY: 60064 AN XY: 74344

African (AFR) AF: 0.878 AC: 36432 AN: 41506

American (AMR) AF: 0.845 AC: 12915 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 3008 AN: 3472

East Asian (EAS) AF: 0.839 AC: 4334 AN: 5166

South Asian (SAS) AF: 0.866 AC: 4173 AN: 4818

European-Finnish (FIN) AF: 0.726 AC: 7664 AN: 10560

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51919 AN: 67996

Other (OTH) AF: 0.824 AC: 1738 AN: 2108

Alfa AF: 0.793 Hom.: 10839

Bravo AF: 0.819

Asia WGS AF: 0.849 AC: 2953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		0.33
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: rs7804865; hg19: chr7-81375854;