chr7-81717369-T-C

Position:

• chr7-81717369-T-C

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002320
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.441

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 43607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-81717369-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGF	NM_000601.6	c.1272-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000222390.11
HGF	NM_001010932.3	c.1257-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGF	ENST00000222390.11	c.1272-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000601.6	P4
HGF	ENST00000457544.7	c.1257-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1

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

GnomAD3 exomes AF: 0.812 AC: 204068 AN: 251290 Hom.: 83243 AF XY: 0.816 AC XY: 110849 AN XY: 135830

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 SAS exome AF: 0.864

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

Gnomad4 AFR exome AF: 0.660

Gnomad4 AMR exome AF: 0.871

Gnomad4 ASJ exome AF: 0.865

Gnomad4 EAS exome AF: 0.882

Gnomad4 SAS exome AF: 0.863

Gnomad4 FIN exome AF: 0.791

Gnomad4 NFE exome AF: 0.791

Gnomad4 OTH exome AF: 0.802

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

Gnomad4 AFR AF: 0.668

Gnomad4 AMR AF: 0.837

Gnomad4 ASJ AF: 0.861

Gnomad4 EAS AF: 0.858

Gnomad4 SAS AF: 0.871

Gnomad4 FIN AF: 0.780

Gnomad4 NFE AF: 0.794

Gnomad4 OTH AF: 0.793

Alfa AF: 0.793 Hom.: 21326

Bravo AF: 0.767

Asia WGS AF: 0.841 AC: 2924 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.795

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	1272-4A>G in Intron 10 of HGF: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce and has been identified in 33.4% (1248/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs1800793). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 39 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Nonsyndromic Hearing Loss, Mixed Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.42
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800793; hg19: chr7-81346685;