Variant chr4-3447925-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000382774.8(HGFAC):c.1526G>A(p.Arg509His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,609,362 control chromosomes in the GnomAD database, including 4,523 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.057 ( 367 hom., cov: 34)

Exomes 𝑓: 0.070 ( 4156 hom. )

Consequence

HGFAC
ENST00000382774.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.59

Variant links:

Genes affected

HGFAC (HGNC:4894): (HGF activator) This gene encodes a member of the peptidase S1 protein family. The encoded protein is first synthesized as an inactive single-chain precursor before being activated to a heterodimeric form by endoproteolytic processing. It acts as serine protease that converts hepatocyte growth factor to the active form. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

HGFAC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022737384).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HGFAC	NM_001528.4 linkuse as main transcript	c.1526G>A	p.Arg509His	missense_variant	12/14	ENST00000382774.8	NP_001519.1
HGFAC	NM_001297439.2 linkuse as main transcript	c.1547G>A	p.Arg516His	missense_variant	13/15		NP_001284368.1
HGFAC	XM_047450155.1 linkuse as main transcript	c.1175G>A	p.Arg392His	missense_variant	12/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HGFAC	ENST00000382774.8 linkuse as main transcript	c.1526G>A	p.Arg509His	missense_variant	12/14	1	NM_001528.4	ENSP00000372224	P2
HGFAC	ENST00000511533.1 linkuse as main transcript	c.1547G>A	p.Arg516His	missense_variant	13/15	1		ENSP00000421801	A2
HGFAC	ENST00000506132.1 linkuse as main transcript	n.566G>A		non_coding_transcript_exon_variant	3/4	2
HGFAC	ENST00000509689.5 linkuse as main transcript	n.1436G>A		non_coding_transcript_exon_variant	7/9	5

Frequencies

GnomAD3 genomes

AF:

0.0575

AC:

8754

AN:

152182

Hom.:

369

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0755

Gnomad ASJ

AF:

0.0772

Gnomad EAS

AF:

0.0914

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0481

Gnomad MID

AF:

0.121

Gnomad NFE

AF:

0.0653

Gnomad OTH

AF:

0.0645

GnomAD3 exomes

AF:

0.0747

AC:

18084

AN:

241986

Hom.:

835

AF XY:

0.0773

AC XY:

10152

AN XY:

131416

show subpopulations

Gnomad AFR exome

AF:

0.0265

Gnomad AMR exome

AF:

0.0741

Gnomad ASJ exome

AF:

0.0849

Gnomad EAS exome

AF:

0.0959

Gnomad SAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.0704

Gnomad OTH exome

AF:

0.0831

GnomAD4 exome

AF:

0.0698

AC:

101724

AN:

1457062

Hom.:

4156

Cov.:

AF XY:

0.0714

AC XY:

51727

AN XY:

724462

show subpopulations

Gnomad4 AFR exome

AF:

0.0265

Gnomad4 AMR exome

AF:

0.0730

Gnomad4 ASJ exome

AF:

0.0850

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.111

Gnomad4 FIN exome

AF:

0.0521

Gnomad4 NFE exome

AF:

0.0663

Gnomad4 OTH exome

AF:

0.0689

GnomAD4 genome

AF:

0.0574

AC:

8744

AN:

152300

Hom.:

367

Cov.:

AF XY:

0.0585

AC XY:

4359

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0277

Gnomad4 AMR

AF:

0.0753

Gnomad4 ASJ

AF:

0.0772

Gnomad4 EAS

AF:

0.0914

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.0481

Gnomad4 NFE

AF:

0.0653

Gnomad4 OTH

AF:

0.0639

Alfa

AF:

0.0682

Hom.:

871

Bravo

AF:

0.0588

TwinsUK

AF:

0.0725

AC:

269

ALSPAC

AF:

0.0706

AC:

272

ESP6500AA

AF:

0.0280

AC:

123

ESP6500EA

AF:

0.0683

AC:

587

ExAC

AF:

0.0725

AC:

8766

Asia WGS

AF:

0.0820

AC:

286

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.81

L;.

MutationTaster

Benign

5.5e-8

P;P

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.26

Sift

Benign

0.20

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.10

B;P

Vest4

0.22

MPC

0.15

ClinPred

0.013

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over