17-13496388-T-C

Position:

• chr17-13496388-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_006042.3(HS3ST3A1):​c.1030A>G​(p.Asn344Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: HS3ST3A1 NM_006042.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity HS3SA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HS3ST3A1	NM_006042.3	c.1030A>G	p.Asn344Asp	missense_variant	2/2	ENST00000284110.2	NP_006033.1
HS3ST3A1	XM_011524114.4	c.433A>G	p.Asn145Asp	missense_variant	3/3		XP_011522416.1
HS3ST3A1	XM_047437228.1	c.433A>G	p.Asn145Asp	missense_variant	2/2		XP_047293184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HS3ST3A1	ENST00000284110.2	c.1030A>G	p.Asn344Asp	missense_variant	2/2	1	NM_006042.3	ENSP00000284110.1
HS3ST3A1	ENST00000578576.1	c.424A>G	p.Asn142Asp	missense_variant	2/2	3		ENSP00000462696.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.1030A>G (p.N344D) 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 1030, causing the asparagine (N) at amino acid position 344 to be replaced by an aspartic acid (D). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.67
Sift	Benign	0.038	D;.
Sift4G	Uncertain	0.034	D;T
Polyphen		0.71	P;.
Vest4		0.89
MutPred		0.60		Gain of sheet (P = 0.0101);.;
MVP		0.29
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.71

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

Other links and lift over

dbSNP: rs1478535664; hg19: chr17-13399705;