7-81717369-T-C

Variant names:

• chr7-81717369-T-C
• rs1800793
• NM_000601.6:c.1272-4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000601.6(HGF):​c.1272-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,611,274 control chromosomes in the GnomAD database, including 512,840 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45338 hom., cov: 31)
  • Exomes 𝑓: 0.80 (467502 hom.)
• Consequence: HGF NM_000601.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002320
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.441
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-81717369-T-C is Benign according to our data. Variant chr7-81717369-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

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.1272-4A>G		splice_region intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.1257-4A>G		splice_region intron	N/A	NP_001010932.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	ENST00000222390.11	TSL:1 MANE Select	c.1272-4A>G		splice_region intron	N/A	ENSP00000222390.5
	HGF	ENST00000457544.7	TSL:1	c.1257-4A>G		splice_region intron	N/A	ENSP00000391238.2
	ENSG00000300407	ENST00000771413.1		n.117+16841T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116866 AN: 151918 Hom.: 45314 Cov.: 31

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.904

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.794

GnomAD2 exomes AF: 0.812 AC: 204068 AN: 251290 AF XY: 0.816

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.874

Gnomad ASJ exome AF: 0.866

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.793

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.799 AC: 1166582 AN: 1459238 Hom.: 467502 Cov.: 38 AF XY: 0.802 AC XY: 582185 AN XY: 726088

African (AFR) AF: 0.660 AC: 22055 AN: 33410

American (AMR) AF: 0.871 AC: 38933 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 22586 AN: 26118

East Asian (EAS) AF: 0.882 AC: 35012 AN: 39678

South Asian (SAS) AF: 0.863 AC: 74410 AN: 86220

European-Finnish (FIN) AF: 0.791 AC: 42205 AN: 53350

Middle Eastern (MID) AF: 0.851 AC: 4901 AN: 5762

European-Non Finnish (NFE) AF: 0.791 AC: 878135 AN: 1109684

Other (OTH) AF: 0.802 AC: 48345 AN: 60302

GnomAD4 genome AF: 0.769 AC: 116936 AN: 152036 Hom.: 45338 Cov.: 31 AF XY: 0.770 AC XY: 57233 AN XY: 74338

African (AFR) AF: 0.668 AC: 27683 AN: 41456

American (AMR) AF: 0.837 AC: 12779 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2985 AN: 3468

East Asian (EAS) AF: 0.858 AC: 4420 AN: 5154

South Asian (SAS) AF: 0.871 AC: 4198 AN: 4818

European-Finnish (FIN) AF: 0.780 AC: 8254 AN: 10578

Middle Eastern (MID) AF: 0.901 AC: 263 AN: 292

European-Non Finnish (NFE) AF: 0.794 AC: 54012 AN: 67984

Other (OTH) AF: 0.793 AC: 1672 AN: 2108

Alfa AF: 0.791 Hom.: 24820

Bravo AF: 0.767

Asia WGS AF: 0.841 AC: 2924 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.795

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 39 (2)
-	-	2	not provided (2)
-	-	1	Nonsyndromic Hearing Loss, Mixed (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.42
DANN	Benign	0.47
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.040		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: rs1800793; hg19: chr7-81346685;