7-81733271-A-T

Variant names:

• chr7-81733271-A-T
• rs757832
• NM_000601.6:c.866-3492T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000601.6(HGF):​c.866-3492T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 151,702 control chromosomes in the GnomAD database, including 41 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 0.021 (41 hom., cov: 32)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 1 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).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0205 (3112/151702) while in subpopulation NFE AF = 0.0299 (2025/67824). AF 95% confidence interval is 0.0288. There are 41 homozygotes in GnomAd4. There are 1463 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.866-3492T>A		intron_variant	Intron 7 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.851-3492T>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.866-3492T>A		intron_variant	Intron 7 of 17	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7	c.851-3492T>A		intron_variant	Intron 7 of 17	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1	n.117+32743A>T		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1	n.172-3710A>T		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3113 AN: 151590 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00513

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0196

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

GnomAD4 genome AF: 0.0205 AC: 3112 AN: 151702 Hom.: 41 Cov.: 32 AF XY: 0.0197 AC XY: 1463 AN XY: 74112

African (AFR) AF: 0.00511 AC: 212 AN: 41470

American (AMR) AF: 0.0175 AC: 266 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00995 AC: 48 AN: 4824

European-Finnish (FIN) AF: 0.0301 AC: 314 AN: 10416

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.0299 AC: 2025 AN: 67824

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0145 Hom.: 2219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		0.010
Mutation Taster		=100/0	polymorphism

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: rs757832; hg19: chr7-81362587;