Genetic Variant HS3ST3A1:p.Lys293Arg (chr17-13496540-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_006042.3(HS3ST3A1):c.878A>G(p.Lys293Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HS3ST3A1
NM_006042.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

HS3ST3A1 (HGNC:5196): (heparan sulfate-glucosamine 3-sulfotransferase 3A1) Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It is a type II integral membrane protein and possesses heparan sulfate glucosaminyl 3-O-sulfotransferase activity. The sulfotransferase domain of this enzyme is highly similar to the same domain of heparan sulfate D-glucosaminyl 3-O-sulfotransferase 3B1, and these two enzymes sulfate an identical disaccharide. This gene is widely expressed, with the most abundant expression in liver and placenta. [provided by RefSeq, Dec 2014]

HS3ST3A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a mutagenesis_site 33.6% loss of enzymatic activity. (size 0) in uniprot entity HS3SA_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.33840322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS3ST3A1	NM_006042.3 link	c.878A>G	p.Lys293Arg	missense_variant	Exon 2 of 2	ENST00000284110.2	NP_006033.1	Q9Y663
HS3ST3A1	XM_011524114.4 link	c.281A>G	p.Lys94Arg	missense_variant	Exon 3 of 3		XP_011522416.1
HS3ST3A1	XM_047437228.1 link	c.281A>G	p.Lys94Arg	missense_variant	Exon 2 of 2		XP_047293184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HS3ST3A1	ENST00000284110.2 link	c.878A>G	p.Lys293Arg	missense_variant	Exon 2 of 2	1	NM_006042.3	ENSP00000284110.1		Q9Y663
HS3ST3A1	ENST00000578576.1 link	c.272A>G	p.Lys91Arg	missense_variant	Exon 2 of 2	3		ENSP00000462696.1		J3KSX5

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150270

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

163516

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

88380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000300

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000210

AC:

AN:

1384082

Hom.:

Cov.:

AF XY:

0.0000204

AC XY:

AN XY:

687196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000332

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:

0.0000265

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000665

AC:

AN:

150270

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73310

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.878A>G (p.K293R) alteration is located in exon 2 (coding exon 2) of the HS3ST3A1 gene. This alteration results from a A to G substitution at nucleotide position 878, causing the lysine (K) at amino acid position 293 to be replaced by an arginine (R). 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

0.099

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.11

Sift

Benign

0.33

T;.

Sift4G

Benign

0.47

T;T

Polyphen

0.0010

B;.

Vest4

0.49

MutPred

0.35

Loss of methylation at K293 (P = 0.0401);.;

MVP

0.040

ClinPred

0.53

GERP RS

5.3

Varity_R

0.36

gMVP

0.35

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