7-81740103-A-G

Variant names:

• chr7-81740103-A-G
• rs12707453
• NM_000601.6:c.865+3250T>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.865+3250T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,202 control chromosomes in the GnomAD database, including 1,925 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 0.14 (1925 hom., cov: 31)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.794
• Publications: 11 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6	c.865+3250T>C		intron_variant	Intron 7 of 17	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3	c.850+3250T>C		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.865+3250T>C		intron_variant	Intron 7 of 17	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7	c.850+3250T>C		intron_variant	Intron 7 of 17	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1	n.117+39575A>G		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1	n.281-2792A>G		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21425 AN: 152084 Hom.: 1923 Cov.: 31

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.141 AC: 21409 AN: 152202 Hom.: 1925 Cov.: 31 AF XY: 0.139 AC XY: 10337 AN XY: 74420

African (AFR) AF: 0.0368 AC: 1531 AN: 41558

American (AMR) AF: 0.187 AC: 2851 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3470

East Asian (EAS) AF: 0.311 AC: 1604 AN: 5164

South Asian (SAS) AF: 0.228 AC: 1096 AN: 4816

European-Finnish (FIN) AF: 0.0836 AC: 887 AN: 10606

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12038 AN: 67992

Other (OTH) AF: 0.172 AC: 364 AN: 2112

Alfa AF: 0.174 Hom.: 4380

Bravo AF: 0.147

Asia WGS AF: 0.218 AC: 758 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.9
DANN	Benign	0.72
PhyloP100		0.79
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: rs12707453; hg19: chr7-81369419;