chr7-81717369-T-C

Variant names:

Variant summary

Our verdict is The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The NM_000601.6(HGF):c.1272-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.797 (AC=1,283,518) in the gnomAD database across 1,611,274 control chromosomes, including 512,840 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.875. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45338 hom., cov: 31)

Exomes 𝑓: 0.80 ( 467502 hom. )

Consequence

HGF
NM_000601.6 splice_region, intron

Scores

Splicing: ADA: 0.0002289

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.441

Publications

22 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):

lymphedema
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
autosomal recessive nonsyndromic hearing loss 39
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
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

new If you want to explore the variant's impact on the transcript NM_000601.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -16 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (10/10 total B/LB).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8747 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000601.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGF	NM_000601.6	MANE Select	c.1272-4A>G		splice_region intron	N/A	NP_000592.3
	HGF	NM_001010932.3		c.1257-4A>G		splice_region intron	N/A	NP_001010932.1	P14210-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HGF	ENST00000222390.11	TSL:1 MANE Select	c.1272-4A>G	splice_region intron	N/A	ENSP00000222390.5	P14210-1
HGF	ENST00000457544.7	TSL:1	c.1257-4A>G	splice_region intron	N/A	ENSP00000391238.2	P14210-3
ENSG00000300407	ENST00000771413.1		n.117+16841T>C	intron	N/A

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

GnomAD2 exomes

AF:

0.812

AC:

204068

AN:

251290

AF XY:

0.816

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 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

African (AFR)

AF:

0.660

AC:

22055

AN:

33410

American (AMR)

AF:

0.871

AC:

38933

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.865

AC:

22586

AN:

26118

East Asian (EAS)

AF:

0.882

AC:

35012

AN:

39678

South Asian (SAS)

AF:

0.863

AC:

74410

AN:

86220

European-Finnish (FIN)

AF:

0.791

AC:

42205

AN:

53350

Middle Eastern (MID)

AF:

0.851

AC:

4901

AN:

5762

European-Non Finnish (NFE)

AF:

0.791

AC:

878135

AN:

1109684

Other (OTH)

AF:

0.802

AC:

48345

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

11151

22303

33454

44606

55757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20672

41344

62016

82688

103360

<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:

0.769

AC:

116936

AN:

152036

Hom.:

45338

Cov.:

AF XY:

0.770

AC XY:

57233

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.668

AC:

27683

AN:

41456

American (AMR)

AF:

0.837

AC:

12779

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.861

AC:

2985

AN:

3468

East Asian (EAS)

AF:

0.858

AC:

4420

AN:

5154

South Asian (SAS)

AF:

0.871

AC:

4198

AN:

4818

European-Finnish (FIN)

AF:

0.780

AC:

8254

AN:

10578

Middle Eastern (MID)

AF:

0.901

AC:

263

AN:

292

European-Non Finnish (NFE)

AF:

0.794

AC:

54012

AN:

67984

Other (OTH)

AF:

0.793

AC:

1672

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1389

2778

4168

5557

6946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<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:

0.791

Hom.:

24820

Bravo

AF:

0.767

Asia WGS

AF:

0.841

AC:

2924

AN:

3478

EpiCase

AF:

0.793

EpiControl

AF:

0.795

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.903

AC:

110372

AN:

122276

Turkish Variome

AF:

0.834

AC:

5606

AN:

6718

Hom.:

2363

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.851

AC:

7629

AN:

8960

Hom.:

3255

ABraOM SABE-WGS-1171

AF:

0.787

AC:

1842

AN:

2342

Hom.:

728

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Autosomal recessive nonsyndromic hearing loss 39 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.42

(source)

DANN

Benign

0.47

PhyloP100

-0.44

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over