7-81717369-T-C

Position:

chr7-81717369-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:9

Conservation

PhyloP100: -0.441

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1272-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000222390.11
HGF	NM_001010932.3 linkuse as main transcript	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 linkuse as main transcript	c.1272-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000601.6	P4	P14210-1
HGF	ENST00000457544.7 linkuse as main transcript	c.1257-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1	P14210-3

Frequencies

GnomAD3 genomes

AF:

0.769

AC:

116866

AN:

151918

Hom.:

45314

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.802

AC XY:

582185

AN XY:

726088

show subpopulations

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.:

AF XY:

0.770

AC XY:

57233

AN XY:

74338

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	-	- -

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	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over