Genetic Variant HGF:c.1169-2423C>T (chr7-81723270-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000601.6(HGF):c.1169-2423C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 152,044 control chromosomes in the GnomAD database, including 50,884 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.82 ( 50884 hom., cov: 32)

Consequence

HGF
NM_000601.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.841

Publications

4 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGF	NM_000601.6 link	c.1169-2423C>T		intron_variant	Intron 9 of 17	ENST00000222390.11	NP_000592.3	P14210-1
HGF	NM_001010932.3 link	c.1154-2423C>T		intron_variant	Intron 9 of 17		NP_001010932.1	P14210-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGF	ENST00000222390.11 link	c.1169-2423C>T		intron_variant	Intron 9 of 17	1	NM_000601.6	ENSP00000222390.5		P14210-1

Frequencies

GnomAD3 genomes

AF:

0.818

AC:

124219

AN:

151928

Hom.:

50839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.811

Gnomad AMI

AF:

0.705

Gnomad AMR

AF:

0.850

Gnomad ASJ

AF:

0.885

Gnomad EAS

AF:

0.854

Gnomad SAS

AF:

0.870

Gnomad FIN

AF:

0.807

Gnomad MID

AF:

0.904

Gnomad NFE

AF:

0.807

Gnomad OTH

AF:

0.822

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.818

AC:

124322

AN:

152044

Hom.:

50884

Cov.:

AF XY:

0.818

AC XY:

60799

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.811

AC:

33640

AN:

41484

American (AMR)

AF:

0.850

AC:

12972

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.885

AC:

3074

AN:

3472

East Asian (EAS)

AF:

0.854

AC:

4421

AN:

5178

South Asian (SAS)

AF:

0.870

AC:

4192

AN:

4820

European-Finnish (FIN)

AF:

0.807

AC:

8512

AN:

10554

Middle Eastern (MID)

AF:

0.900

AC:

261

AN:

290

European-Non Finnish (NFE)

AF:

0.807

AC:

54876

AN:

67960

Other (OTH)

AF:

0.820

AC:

1731

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1200

2400

3599

4799

5999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.821

Hom.:

6501

Bravo

AF:

0.819

Asia WGS

AF:

0.852

AC:

2962

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.87

(source)

DANN

Benign

0.53

PhyloP100

-0.84

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over