chrX-132669135-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001394073.1(HS6ST2):​c.1045C>T​(p.Arg349Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,202,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000016 ( 0 hom. 7 hem. )

Consequence

HS6ST2
NM_001394073.1 missense

Scores

1
2
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63
Variant links:
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]
HS6ST2-AS1 (HGNC:40870): (HS6ST2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12962854).
BS2
High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HS6ST2NM_001394073.1 linkuse as main transcriptc.1045C>T p.Arg349Trp missense_variant 4/5 ENST00000370833.7 NP_001381002.1
HS6ST2-AS1NR_046691.1 linkuse as main transcriptn.225-428G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HS6ST2ENST00000370833.7 linkuse as main transcriptc.1045C>T p.Arg349Trp missense_variant 4/55 NM_001394073.1 ENSP00000359870 Q96MM7-4
HS6ST2-AS1ENST00000455269.1 linkuse as main transcriptn.225-428G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000180
AC:
2
AN:
111355
Hom.:
0
Cov.:
23
AF XY:
0.0000298
AC XY:
1
AN XY:
33565
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:
0.000280
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000394
AC:
7
AN:
177496
Hom.:
0
AF XY:
0.0000154
AC XY:
1
AN XY:
64958
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000751
Gnomad SAS exome
AF:
0.0000541
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000508
Gnomad OTH exome
AF:
0.000228
GnomAD4 exome
AF:
0.0000156
AC:
17
AN:
1091596
Hom.:
0
Cov.:
27
AF XY:
0.0000196
AC XY:
7
AN XY:
357382
show subpopulations
Gnomad4 AFR exome
AF:
0.0000381
Gnomad4 AMR exome
AF:
0.0000285
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000332
Gnomad4 SAS exome
AF:
0.0000186
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000143
Gnomad4 OTH exome
AF:
0.0000218
GnomAD4 genome
AF:
0.0000180
AC:
2
AN:
111355
Hom.:
0
Cov.:
23
AF XY:
0.0000298
AC XY:
1
AN XY:
33565
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000280
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000496
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 13, 2023The c.1045C>T (p.R349W) alteration is located in exon 5 (coding exon 4) of the HS6ST2 gene. This alteration results from a C to T substitution at nucleotide position 1045, causing the arginine (R) at amino acid position 349 to be replaced by a tryptophan (W). 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
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
21
DANN
Pathogenic
1.0
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.63
.;T;T
M_CAP
Benign
0.069
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.73
T
MutationTaster
Benign
1.0
D;D;D;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.86
N;.;.
REVEL
Benign
0.18
Sift
Uncertain
0.0010
D;.;.
Sift4G
Uncertain
0.0020
D;D;.
Vest4
0.38
MVP
0.77
MPC
1.4
ClinPred
0.37
T
GERP RS
3.2
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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.

Other links and lift over

dbSNP: rs761023821; hg19: chrX-131803163; API