Variant 4-3442861-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001528.4(HGFAC):c.247C>T(p.Leu83Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,574,940 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 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

HGFAC
NM_001528.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.749

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03911683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4 link	c.247C>T	p.Leu83Phe	missense_variant	2/14	ENST00000382774.8	NP_001519.1	Q04756
HGFAC	NM_001297439.2 link	c.247C>T	p.Leu83Phe	missense_variant	2/15		NP_001284368.1	Q04756D6RAR4
HGFAC	XM_047450155.1 link	c.-105C>T		5_prime_UTR_variant	2/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8 link	c.247C>T	p.Leu83Phe	missense_variant	2/14	1	NM_001528.4	ENSP00000372224.4		Q04756
HGFAC	ENST00000511533.1 link	c.247C>T	p.Leu83Phe	missense_variant	2/15	1		ENSP00000421801.1		D6RAR4

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

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:

0.0000282

AC:

AN:

212932

Hom.:

AF XY:

0.00000861

AC XY:

AN XY:

116176

show subpopulations

Gnomad AFR exome

AF:

0.000397

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1422774

Hom.:

Cov.:

AF XY:

0.0000312

AC XY:

AN XY:

706166

show subpopulations

Gnomad4 AFR exome

AF:

0.00121

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.000204

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000724

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:

0.0000987

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

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

Dec 07, 2023

The c.247C>T (p.L83F) alteration is located in exon 2 (coding exon 2) of the HGFAC gene. This alteration results from a C to T substitution at nucleotide position 247, causing the leucine (L) at amino acid position 83 to be replaced by a phenylalanine (F). 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

0.067

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.2

DANN

Benign

0.84

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.40

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.34

N;N

REVEL

Benign

0.15

Sift

Benign

0.15

T;T

Sift4G

Uncertain

0.023

D;D

Polyphen

0.0020

B;B

Vest4

0.075

MVP

0.41

MPC

0.045

ClinPred

0.010

GERP RS

0.14

Varity_R

0.044

gMVP

0.26

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