X-132628521-T-G

Variant names:

• chrX-132628521-T-G
• rs368413228
• NM_001394073.1:c.1640A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001394073.1(HS6ST2):​c.1640A>C​(p.His547Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,209,252 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.000043 (0 hom. 12 hem.)
• Consequence: HS6ST2 NM_001394073.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Paganini-Miozzo syndrome

  Inheritance: Unknown, XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000296977 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30805698).
• BS2: High Hemizygotes in GnomAd4 at 11 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394073.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS6ST2	NM_001394073.1	MANE Select	c.1640A>C	p.His547Pro	missense	Exon 5 of 5	NP_001381002.1	Q96MM7-4
	HS6ST2	NM_001077188.2		c.1640A>C	p.His547Pro	missense	Exon 6 of 6	NP_001070656.1	Q96MM7-4
	HS6ST2	NM_001394074.1		c.1520A>C	p.His507Pro	missense	Exon 3 of 3	NP_001381003.1	Q96MM7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS6ST2	ENST00000370833.7	TSL:5 MANE Select	c.1640A>C	p.His547Pro	missense	Exon 5 of 5	ENSP00000359870.3	Q96MM7-4
	HS6ST2	ENST00000406696.5	TSL:1	c.1202A>C	p.His401Pro	missense	Exon 5 of 5	ENSP00000384013.5	Q96MM7-3
	HS6ST2	ENST00000521489.5	TSL:5	c.1640A>C	p.His547Pro	missense	Exon 6 of 6	ENSP00000429473.1	Q96MM7-4

Frequencies

GnomAD3 genomes AF: 0.000387 AC: 43 AN: 111253 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000830 AC: 15 AN: 180785 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000428 AC: 47 AN: 1097999 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 12 AN XY: 363465

African (AFR) AF: 0.00117 AC: 31 AN: 26401

American (AMR) AF: 0.0000852 AC: 3 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30189

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841975

Other (OTH) AF: 0.000239 AC: 11 AN: 46075

GnomAD4 genome AF: 0.000387 AC: 43 AN: 111253 Hom.: 0 Cov.: 23 AF XY: 0.000329 AC XY: 11 AN XY: 33421

African (AFR) AF: 0.00134 AC: 41 AN: 30495

American (AMR) AF: 0.000192 AC: 2 AN: 10434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2621

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5979

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53131

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.000592 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000993 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.56
Sift	Benign	0.030	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.58
MVP		0.89
MPC		2.0
ClinPred		0.15	T
GERP RS		6.0
Varity_R		0.82
gMVP		0.88
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs368413228; hg19: chrX-131762549;