NM_000601.6:c.333A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000601.6(HGF):c.333A>G(p.Glu111Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,612,428 control chromosomes in the GnomAD database, including 3,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 1859 hom., cov: 32)

Exomes 𝑓: 0.019 ( 1930 hom. )

Consequence

HGF
NM_000601.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.990

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 7-81758726-T-C is Benign according to our data. Variant chr7-81758726-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6 link	c.333A>G	p.Glu111Glu	synonymous_variant	Exon 3 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.333A>G	p.Glu111Glu	synonymous_variant	Exon 3 of 18	1	NM_000601.6	ENSP00000222390.5		P14210-1

Frequencies

GnomAD3 genomes

AF:

0.0922

AC:

14017

AN:

152024

Hom.:

1854

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0414

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00963

Gnomad SAS

AF:

0.0767

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.00861

Gnomad OTH

AF:

0.0649

GnomAD2 exomes

AF:

0.0362

AC:

9106

AN:

251234

AF XY:

0.0332

show subpopulations

Gnomad AFR exome

AF:

0.293

Gnomad AMR exome

AF:

0.0224

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.00925

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00851

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0193

AC:

28241

AN:

1460286

Hom.:

1930

Cov.:

AF XY:

0.0200

AC XY:

14504

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.302

AC:

10084

AN:

33374

American (AMR)

AF:

0.0244

AC:

1090

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00939

AC:

245

AN:

26104

East Asian (EAS)

AF:

0.00733

AC:

290

AN:

39548

South Asian (SAS)

AF:

0.0690

AC:

5949

AN:

86194

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.0460

AC:

265

AN:

5758

European-Non Finnish (NFE)

AF:

0.00741

AC:

8232

AN:

1110888

Other (OTH)

AF:

0.0333

AC:

2010

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1120

2240

3361

4481

5601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.0924

AC:

14058

AN:

152142

Hom.:

1859

Cov.:

AF XY:

0.0912

AC XY:

6783

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.294

AC:

12218

AN:

41488

American (AMR)

AF:

0.0413

AC:

632

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00965

AC:

AN:

5182

South Asian (SAS)

AF:

0.0755

AC:

364

AN:

4822

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00861

AC:

585

AN:

67954

Other (OTH)

AF:

0.0643

AC:

136

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

512

1024

1535

2047

2559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0405

Hom.:

1822

Bravo

AF:

0.103

Asia WGS

AF:

0.0690

AC:

240

AN:

3470

EpiCase

AF:

0.00987

EpiControl

AF:

0.0107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glu111Glu in Exon 03 of HGF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 27.9% (1043/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs5745635). -

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 24, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.7

(source)

DANN

Benign

0.48

PhyloP100

-0.99

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