Variant 4-3443122-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001528.4(HGFAC):c.371C>T(p.Ser124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,581,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HGFAC
NM_001528.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.261

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12696692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4 linkuse as main transcript	c.371C>T	p.Ser124Leu	missense_variant	3/14	ENST00000382774.8	NP_001519.1	Q04756
HGFAC	NM_001297439.2 linkuse as main transcript	c.371C>T	p.Ser124Leu	missense_variant	3/15		NP_001284368.1	Q04756D6RAR4
HGFAC	XM_047450155.1 linkuse as main transcript	c.20C>T	p.Ser7Leu	missense_variant	3/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8 linkuse as main transcript	c.371C>T	p.Ser124Leu	missense_variant	3/14	1	NM_001528.4	ENSP00000372224.4		Q04756
HGFAC	ENST00000511533.1 linkuse as main transcript	c.371C>T	p.Ser124Leu	missense_variant	3/15	1		ENSP00000421801.1		D6RAR4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000971

AC:

AN:

205992

Hom.:

AF XY:

0.00000882

AC XY:

AN XY:

113332

show subpopulations

Gnomad AFR exome

AF:

0.0000703

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000231

AC:

AN:

1429092

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

710224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000611

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000365

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.0000218

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000660

Hom.:

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.371C>T (p.S124L) alteration is located in exon 3 (coding exon 3) of the HGFAC gene. This alteration results from a C to T substitution at nucleotide position 371, causing the serine (S) at amino acid position 124 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.045

T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.25

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;.

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.038

Sift

Benign

0.55

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0080

B;B

Vest4

0.18

MutPred

0.72

Loss of catalytic residue at S124 (P = 5e-04);Loss of catalytic residue at S124 (P = 5e-04);

MVP

0.30

MPC

0.040

ClinPred

0.020

GERP RS

1.3

Varity_R

0.033

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over