Variant 4-3444060-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001528.4(HGFAC):c.497C>G(p.Ser166Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HGFAC
NM_001528.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.225

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGFAC	NM_001528.4 linkuse as main transcript	c.497C>G	p.Ser166Cys	missense_variant	5/14	ENST00000382774.8	NP_001519.1	Q04756
HGFAC	NM_001297439.2 linkuse as main transcript	c.497C>G	p.Ser166Cys	missense_variant	5/15		NP_001284368.1	Q04756D6RAR4
HGFAC	XM_047450155.1 linkuse as main transcript	c.146C>G	p.Ser49Cys	missense_variant	5/14		XP_047306111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGFAC	ENST00000382774.8 linkuse as main transcript	c.497C>G	p.Ser166Cys	missense_variant	5/14	1	NM_001528.4	ENSP00000372224.4		Q04756
HGFAC	ENST00000511533.1 linkuse as main transcript	c.497C>G	p.Ser166Cys	missense_variant	5/15	1		ENSP00000421801.1		D6RAR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1456452

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jun 17, 2022

The c.497C>G (p.S166C) alteration is located in exon 5 (coding exon 5) of the HGFAC gene. This alteration results from a C to G substitution at nucleotide position 497, causing the serine (S) at amino acid position 166 to be replaced by a cysteine (C). 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.0041

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

N;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

1.0

D;D

Vest4

0.42

MutPred

0.38

Loss of glycosylation at S166 (P = 0.0045);Loss of glycosylation at S166 (P = 0.0045);

MVP

0.94

MPC

0.29

ClinPred

0.91

GERP RS

3.7

Varity_R

0.17

gMVP

0.43

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over