rs5745764

Variant names:

• chr7-81702917-T-C
• rs5745764
• NM_000601.6:c.2011-160A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000601.6(HGF):​c.2011-160A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 151,880 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0095 (20 hom., cov: 32)
• Consequence: HGF NM_000601.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.548
• Publications: 0 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: G2P, Ambry Genetics, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-81702917-T-C is Benign according to our data. Variant chr7-81702917-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1205115.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00945 (1436/151880) while in subpopulation AFR AF = 0.033 (1371/41530). AF 95% confidence interval is 0.0316. There are 20 homozygotes in GnomAd4. There are 671 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000601.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	NM_000601.6	MANE Select	c.2011-160A>G		intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.1996-160A>G		intron	N/A	NP_001010932.1	P14210-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	ENST00000222390.11	TSL:1 MANE Select	c.2011-160A>G		intron	N/A	ENSP00000222390.5	P14210-1
	HGF	ENST00000457544.7	TSL:1	c.1996-160A>G		intron	N/A	ENSP00000391238.2	P14210-3
	ENSG00000300407	ENST00000771413.1		n.117+2389T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00946 AC: 1435 AN: 151762 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00362

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00287

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

GnomAD4 genome AF: 0.00945 AC: 1436 AN: 151880 Hom.: 20 Cov.: 32 AF XY: 0.00904 AC XY: 671 AN XY: 74252

African (AFR) AF: 0.0330 AC: 1371 AN: 41530

American (AMR) AF: 0.00362 AC: 55 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67750

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00717 Hom.: 3

Bravo AF: 0.0103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-0.55
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: rs5745764; hg19: chr7-81332233;