Variant 4-3442041-C-G 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.40C>G(p.Pro14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,529,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

HGFAC
NM_001528.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0330

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=0.10790399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/14	ENST00000382774.8	NP_001519.1	Q04756
HGFAC	NM_001297439.2 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/15		NP_001284368.1	Q04756D6RAR4
HGFAC	XM_047450155.1 linkuse as main transcript	c.-235+222C>G		intron_variant			XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/14	1	NM_001528.4	ENSP00000372224.4		Q04756
HGFAC	ENST00000511533.1 linkuse as main transcript	c.40C>G	p.Pro14Ala	missense_variant	1/15	1		ENSP00000421801.1		D6RAR4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000305

AC:

AN:

163720

Hom.:

AF XY:

0.0000213

AC XY:

AN XY:

93782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000499

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000363

AC:

AN:

1377698

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

684740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000354

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000116

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000861

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

Oct 20, 2023

The c.40C>G (p.P14A) alteration is located in exon 1 (coding exon 1) of the HGFAC gene. This alteration results from a C to G substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by an alanine (A). 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

0.051

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.28

CADD

Benign

2.8

DANN

Benign

0.52

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.37

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.97

L;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.085

Sift

Benign

0.081

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0030

B;B

Vest4

0.29

MutPred

0.40

Loss of glycosylation at P14 (P = 0.0092);Loss of glycosylation at P14 (P = 0.0092);

MVP

0.79

MPC

0.042

ClinPred

0.091

GERP RS

2.0

Varity_R

0.043

gMVP

0.086

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

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