7-81762824-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000601.6(HGF):c.137C>T(p.Ala46Val) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,596,858 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

HGF
NM_000601.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.49

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009344757).

BP6

Variant 7-81762824-G-A is Benign according to our data. Variant chr7-81762824-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360784.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}. Variant chr7-81762824-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6 link	c.137C>T	p.Ala46Val	missense_variant	Exon 2 of 18	ENST00000222390.11	NP_000592.3	P14210-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11 link	c.137C>T	p.Ala46Val	missense_variant	Exon 2 of 18	1	NM_000601.6	ENSP00000222390.5		P14210-1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

202

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00178

AC:

446

AN:

250740

Hom.:

AF XY:

0.00179

AC XY:

242

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000638

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00182

AC:

2632

AN:

1444754

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1269

AN XY:

719900

show subpopulations

Gnomad4 AFR exome

AF:

0.000423

Gnomad4 AMR exome

AF:

0.000627

Gnomad4 ASJ exome

AF:

0.00542

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000489

Gnomad4 FIN exome

AF:

0.00238

Gnomad4 NFE exome

AF:

0.00200

Gnomad4 OTH exome

AF:

0.00144

GnomAD4 genome

AF:

0.00133

AC:

202

AN:

152104

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00221

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00180

AC:

218

EpiCase

AF:

0.00185

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 29924831) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 17, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HGF p.Ala46Val variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs150267054), ClinVar (classified as a VUS by Illumina for Nonsyndromic Hearing Loss, Mixed and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS and likely benign). The variant was also identified in control databases in 482 of 282092 chromosomes at a frequency of 0.001709 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 53 of 10362 chromosomes (freq: 0.005115), European (Finnish) in 66 of 25094 chromosomes (freq: 0.00263), European (non-Finnish) in 320 of 128720 chromosomes (freq: 0.002486), Other in 5 of 7206 chromosomes (freq: 0.000694), Latino in 22 of 35338 chromosomes (freq: 0.000623), South Asian in 10 of 30548 chromosomes (freq: 0.000327) and African in 6 of 24922 chromosomes (freq: 0.000241) but was not observed in the East Asian population. The p.Ala46 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Nonsyndromic Hearing Loss, Mixed

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2016

p.Ala46Val in exon 2 of HGF: This variant is not expected to have clinical signi ficance because it has been identified in 0.3% (196/64768) of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs150267054). -

HGF-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D;.;.;.;.;.;D;D;.;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.0093

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.6

L;L;L;L;L;L;.;.;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.0

.;N;N;N;N;N;.;N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.17

.;T;T;T;T;T;.;T;.;T;D

Sift4G

Benign

0.29

.;T;T;T;T;T;.;D;.;.;.

Polyphen

0.96

D;D;P;P;P;.;.;.;.;.;.

Vest4

0.31, 0.33, 0.35, 0.35, 0.32, 0.32

MVP

0.64

MPC

1.1

ClinPred

0.019

GERP RS

5.9

Varity_R

0.76

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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