rs199538589

Positions:

chr2-128268254-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004807.3(HS6ST1):c.1144C>T(p.Arg382Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,611,496 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 19 hom. )

Consequence

HS6ST1
NM_004807.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:2B:5O:1

Conservation

PhyloP100: 5.54

Variant links:

Genes affected

HS6ST1 (HGNC:5201): (heparan sulfate 6-O-sulfotransferase 1) The protein encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biological activities. This enzyme is a type II integral membrane protein and is responsible for 6-O-sulfation of heparan sulfate. This enzyme does not share significant sequence similarity with other known sulfotransferases. A pseudogene located on chromosome 1 has been found for this gene. [provided by RefSeq, Jul 2008]

HS6ST1 links:

HS6ST1 (HGNC:):

HS6ST1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018632412).

BP6

Variant 2-128268254-G-A is Benign according to our data. Variant chr2-128268254-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 180161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR,Digenic,Multigenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HS6ST1	NM_004807.3 linkuse as main transcript	c.1144C>T	p.Arg382Trp	missense_variant	2/2	ENST00000259241.7	NP_004798.3	O60243-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HS6ST1	ENST00000259241.7 linkuse as main transcript	c.1144C>T	p.Arg382Trp	missense_variant	2/2	1	NM_004807.3	ENSP00000259241.6		O60243-1
HS6ST1	ENST00000469019.1 linkuse as main transcript	n.361-21729C>T		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00188

AC:

464

AN:

246850

Hom.:

AF XY:

0.00251

AC XY:

337

AN XY:

134514

show subpopulations

Gnomad AFR exome

AF:

0.000524

Gnomad AMR exome

AF:

0.000900

Gnomad ASJ exome

AF:

0.00351

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.000501

GnomAD4 exome

AF:

0.00122

AC:

1774

AN:

1459198

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1128

AN XY:

725838

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00322

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000455

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.000998

AC:

152

AN:

152298

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0122

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000767

ESP6500AA

AF:

0.000731

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.00213

AC:

257

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:2Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	This variant is associated with the following publications: (PMID: 21700882, 23643382, 26207952, 27535533, 30669598) -
Uncertain significance, flagged submission	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The HS6ST1 p.R382W variant was identified in 5 of 1590 proband chromosomes (frequency: 0.00314) from individuals or families with idiopathic hypogonadotropic hypogonadism (Zhu_2015_PMID:25636053, Miraoui_2013_PMID:23643382, Tornberg_2011_PMID:21700882). The variant was identified in dbSNP (ID: rs199538589) and in ClinVar (classified as likely pathogenic by the Chan Lab at Boston Children's Hospital and benign by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine with the associated condition of hypogonadotrophic hypogonadism). The variant was also identified in control databases in 480 of 278216 chromosomes (3 homozygous) at a frequency of 0.001725 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 337 of 30560 chromosomes (freq: 0.01103), Ashkenazi Jewish in 35 of 10268 chromosomes (freq: 0.003409), Latino in 31 of 35288 chromosomes (freq: 0.000879), African in 16 of 23958 chromosomes (freq: 0.000668), European (non-Finnish) in 56 of 126664 chromosomes (freq: 0.000442), Other in 3 of 7078 chromosomes (freq: 0.000424) and East Asian in 2 of 19480 chromosomes (freq: 0.000103), but was not observed in the European (Finnish) population. The p.Arg382 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In vitro functional analysis demonstrated a 25 to 35% reduction in enzymatic activity with the p.R382W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the p.R382W mutant displayed a reduced capacity to rescue a kal1-dependent axon branching phenotype compared to wildtype HS6ST1 (Tornberg_2011_PMID:21700882). Tornberg et al. (2011) identified the p.R382W variant in three unrelated individuals with hypogonadotropic hypogonadism: a female and two males (1 with anosmia and 2 with a normal sense of smell). The female proband had a brother with delayed puberty who did not carry the HS6ST1 p.R382W mutation, whereas the anosmic male proband had an unaffected brother who did carry the mutation, indicating that the variant did not segregate with disease (Tornberg_2011_PMID:21700882). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -

Hypogonadotropic hypogonadism 7 with or without anosmia

Pathogenic:1Benign:1

Likely pathogenic, flagged submission	case-control	Chan Lab, Boston Children's Hospital	Nov 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

HS6ST1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The HS6ST1 c.1144C>T variant is predicted to result in the amino acid substitution p.Arg382Trp. This variant has been reported in multiple unrelated patients with hypogonadotropic hypogonadism (referred to as R372W in Tornberg et al. 2011. PubMed ID: 21700882; Miraoui et al. 2013. PubMed ID: 23643382; Zhu et al. 2015. PubMed ID: 25636053), and was defined as a founder allele in Caucasian and South Asian ethnicities (Choi et al. 2015. PubMed ID: 26207952, Table 2). In vitro and in vivo functional studies showed that the p.Arg382Trp variant resulted in reduced enzymatic activity compared to wild-type (referred to as R372W in Tornberg et al. 2011. PubMed ID: 21700882). However, this variant is found at an allele frequency of up to ~1.12% in South Asian individuals (including 3 homozygotes) in a large population database of individuals with unknown phenotype, which is likely too common to be a primary cause of autosomal dominant disease. Of note, in a recent publication, this variant was found in a patient with milder adult-onset form of hypogonadotropic hypogonadism (Cangiano et al. 2019. PubMed ID: 30669598, Table S1). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, unrelated to patient disease -

Hypogonadotropic hypogonadism 15 with or without anosmia

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg382Trp variant in HS6ST1 has been identified in 6 individuals with idiopathic hypogonadotropic hypogonadism (PMID: 21700882, 23643382), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg382Trp variant may silghtly impact protein function (PMID: 21700882). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal dominant idiopathic hypogonadotropic hypogonadism. -

HYPOGONADOTROPIC HYPOGONADISM 15 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 12, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.85

MVP

0.82

ClinPred

0.027

GERP RS

4.5

Varity_R

0.20

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over