X-132628630-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001394073.1(HS6ST2):c.1531G>A(p.Glu511Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,209,569 control chromosomes in the GnomAD database, including 166 homozygotes. There are 6,935 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (5 hom., 363 hem., cov: 23)
  • Exomes 𝑓: 0.019 (161 hom. 6572 hem.)
• Consequence: HS6ST2 NM_001394073.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.74

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030495226).
• BP6: Variant X-132628630-C-T is Benign according to our data. Variant chrX-132628630-C-T is described in ClinVar as [Benign]. Clinvar id is 3037872.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-132628630-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1336/111669) while in subpopulation NFE AF= 0.0197 (1046/53153). AF 95% confidence interval is 0.0187. There are 5 homozygotes in gnomad4. There are 363 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HS6ST2	NM_001394073.1	c.1531G>A	p.Glu511Lys	missense_variant	5/5	ENST00000370833.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HS6ST2	ENST00000370833.7	c.1531G>A	p.Glu511Lys	missense_variant	5/5	5	NM_001394073.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1335 AN: 111616 Hom.: 5 Cov.: 23 AF XY: 0.0107 AC XY: 363 AN XY: 33796

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00585

Gnomad AMR AF: 0.00534

Gnomad ASJ AF: 0.00904

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00265

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.0119 AC: 2153 AN: 181075 Hom.: 11 AF XY: 0.0120 AC XY: 807 AN XY: 67277

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0188 AC: 20587 AN: 1097900 Hom.: 161 Cov.: 31 AF XY: 0.0181 AC XY: 6572 AN XY: 363370

Gnomad4 AFR exome AF: 0.00220

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0221

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0120 AC: 1336 AN: 111669 Hom.: 5 Cov.: 23 AF XY: 0.0107 AC XY: 363 AN XY: 33859

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.00533

Gnomad4 ASJ AF: 0.00904

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00265

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.0180 Hom.: 778

Bravo AF: 0.0109

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0263 AC: 76

ESP6500AA AF: 0.00318 AC: 10

ESP6500EA AF: 0.0173 AC: 111

ExAC AF: 0.0114 AC: 1379

EpiCase AF: 0.0185

EpiControl AF: 0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HS6ST2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.;T
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.7	L;.;.;L
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;N;.;.
REVEL	Benign	0.17
Sift	Benign	0.10	T;T;.;.
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.32	B;.;.;B
Vest4		0.12
MPC		0.71
ClinPred		0.011	T
GERP RS		5.1
Varity_R		0.37
gMVP		0.39

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: rs145272508; hg19: chrX-131762658;