X-132628586-C-A

Variant summary

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

The NM_001394073.1(HS6ST2):c.1575G>T(p.Met525Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HS6ST2 NM_001394073.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

HS6ST2 (HGNC:19133): (heparan sulfate 6-O-sulfotransferase 2) Heparan sulfate proteoglycans are ubiquitous components of the cell surface, extracellular matrix, and basement membranes, and interact with various ligands to influence cell growth, differentiation, adhesion, and migration. This gene encodes a member of the heparan sulfate (HS) sulfotransferase gene family, which catalyze the transfer of sulfate to HS. Different family members and isoforms are thought to synthesize heparan sulfates with tissue-specific structures and functions. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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/exons	MANE	UniProt
HS6ST2	NM_001394073.1	c.1575G>T	p.Met525Ile	missense_variant	5/5	ENST00000370833.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HS6ST2	ENST00000370833.7	c.1575G>T	p.Met525Ile	missense_variant	5/5	5	NM_001394073.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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

Dec 15, 2022

The c.1575G>T (p.M525I) alteration is located in exon 6 (coding exon 5) of the HS6ST2 gene. This alteration results from a G to T substitution at nucleotide position 1575, causing the methionine (M) at amino acid position 525 to be replaced by an isoleucine (I). 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	0.50
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.20	T;.;.;T
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.20	N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.31	N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.33	T;T;.;.
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.53	P;.;.;P
Vest4		0.52
MutPred		0.64		Loss of disorder (P = 0.205);.;.;Loss of disorder (P = 0.205);
MVP		0.53
MPC		0.80
ClinPred		0.34	T
GERP RS		6.0
Varity_R		0.30
gMVP		0.68

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.

Other links and lift over

hg19: chrX-131762614;