17-13496727-C-G

Variant names:

• chr17-13496727-C-G
• rs749006673
• NM_006042.3:c.691G>C

Variant summary

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

The NM_006042.3(HS3ST3A1):​c.691G>C​(p.Ala231Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HS3ST3A1 NM_006042.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS3ST3A1	NM_006042.3	c.691G>C	p.Ala231Pro	missense_variant	Exon 2 of 2	ENST00000284110.2	NP_006033.1
HS3ST3A1	XM_011524114.4	c.94G>C	p.Ala32Pro	missense_variant	Exon 3 of 3		XP_011522416.1
HS3ST3A1	XM_047437228.1	c.94G>C	p.Ala32Pro	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	c.691G>C	p.Ala231Pro	missense_variant	Exon 2 of 2	1	NM_006042.3	ENSP00000284110.1
HS3ST3A1	ENST00000578576.1	c.85G>C	p.Ala29Pro	missense_variant	Exon 2 of 2	3		ENSP00000462696.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000410 AC: 6 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691G>C (p.A231P) alteration is located in exon 2 (coding exon 2) of the HS3ST3A1 gene. This alteration results from a G to C substitution at nucleotide position 691, causing the alanine (A) at amino acid position 231 to be replaced by a proline (P). 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	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.028	D;.
Sift4G	Benign	0.068	T;T
Polyphen		0.74	P;.
Vest4		0.67
MutPred		0.56		Gain of disorder (P = 0.0415);.;
MVP		0.34
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.96
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: rs749006673; hg19: chr17-13400044;