NM_000601.6:c.910G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000601.6(HGF):c.910G>A(p.Glu304Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,613,660 control chromosomes in the GnomAD database, including 3,071 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 195 hom., cov: 32)

Exomes 𝑓: 0.058 ( 2876 hom. )

Consequence

HGF
NM_000601.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.83

Publications

42 publications found

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 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

HGF links:

ENSG00000300407 (HGNC:):

ENSG00000300407 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023468137).

BP6

Variant 7-81729735-C-T is Benign according to our data. Variant chr7-81729735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6 link	c.910G>A	p.Glu304Lys	missense_variant	Exon 8 of 18	ENST00000222390.11	NP_000592.3
HGF	NM_001010932.3 link	c.895G>A	p.Glu299Lys	missense_variant	Exon 8 of 18		NP_001010932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HGF	ENST00000222390.11 link	c.910G>A	p.Glu304Lys	missense_variant	Exon 8 of 18	1	NM_000601.6	ENSP00000222390.5
HGF	ENST00000457544.7 link	c.895G>A	p.Glu299Lys	missense_variant	Exon 8 of 18	1		ENSP00000391238.2
ENSG00000300407	ENST00000771413.1 link	n.117+29207C>T		intron_variant	Intron 2 of 2
ENSG00000300407	ENST00000771414.1 link	n.172-7246C>T		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.0426

AC:

6474

AN:

151966

Hom.:

196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.0626

Gnomad AMR

AF:

0.0389

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0326

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0645

Gnomad OTH

AF:

0.0493

GnomAD2 exomes

AF:

0.0457

AC:

11485

AN:

251390

AF XY:

0.0467

show subpopulations

Gnomad AFR exome

AF:

0.00849

Gnomad AMR exome

AF:

0.0284

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0375

Gnomad NFE exome

AF:

0.0662

Gnomad OTH exome

AF:

0.0556

GnomAD4 exome

AF:

0.0581

AC:

84949

AN:

1461576

Hom.:

2876

Cov.:

AF XY:

0.0573

AC XY:

41660

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00863

AC:

289

AN:

33478

American (AMR)

AF:

0.0290

AC:

1297

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

3553

AN:

26126

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39690

South Asian (SAS)

AF:

0.0122

AC:

1056

AN:

86256

European-Finnish (FIN)

AF:

0.0389

AC:

2076

AN:

53394

Middle Eastern (MID)

AF:

0.0870

AC:

502

AN:

5768

European-Non Finnish (NFE)

AF:

0.0653

AC:

72608

AN:

1111746

Other (OTH)

AF:

0.0590

AC:

3565

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3949

7898

11846

15795

19744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2630

5260

7890

10520

13150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0425

AC:

6467

AN:

152084

Hom.:

195

Cov.:

AF XY:

0.0398

AC XY:

2957

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0108

AC:

450

AN:

41512

American (AMR)

AF:

0.0387

AC:

590

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

443

AN:

3470

East Asian (EAS)

AF:

0.000583

AC:

AN:

5146

South Asian (SAS)

AF:

0.0108

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0326

AC:

344

AN:

10564

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0645

AC:

4385

AN:

68000

Other (OTH)

AF:

0.0488

AC:

103

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0587

Hom.:

1459

Bravo

AF:

0.0427

TwinsUK

AF:

0.0609

AC:

226

ALSPAC

AF:

0.0703

AC:

271

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0702

AC:

604

ExAC

AF:

0.0447

AC:

5433

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0676

EpiControl

AF:

0.0711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glu304Lys in Exon 08 of HGF: This variant is not expected to have clinical signi ficance because it has been identified in 7.3% (510/7020) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs5745687). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nonsyndromic Hearing Loss, Mixed

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;.

Eigen

Benign

-0.0015

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.91

.;D;D

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.

PhyloP100

1.8

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

.;N;N

REVEL

Benign

0.086

Sift

Benign

0.47

.;T;T

Sift4G

Benign

0.66

.;T;T

Polyphen

0.38

B;B;P

Vest4

0.10, 0.15

MPC

0.67

ClinPred

0.014

GERP RS

4.5

Varity_R

0.29

gMVP

0.81

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over