Genetic Variant HS3ST6:p.Ala206Ser (chr16-1912003-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001009606.4(HS3ST6):c.616G>T(p.Ala206Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,531,610 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 2 hom. )

Consequence

HS3ST6
NM_001009606.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.961

Variant links:

Genes affected

HS3ST6 (HGNC:14178): (heparan sulfate-glucosamine 3-sulfotransferase 6) Predicted to enable [heparan sulfate]-glucosamine 3-sulfotransferase 1 activity. Predicted to be involved in glycosaminoglycan biosynthetic process. Predicted to act upstream of or within blastocyst hatching. Predicted to be located in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

HS3ST6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019818962).

BS2

High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS3ST6	NM_001009606.4 link	c.616G>T	p.Ala206Ser	missense_variant	Exon 2 of 2	ENST00000454677.3	NP_001009606.3	Q96QI5
HS3ST6	XM_011522608.3 link	c.241G>T	p.Ala81Ser	missense_variant	Exon 2 of 2		XP_011520910.1
HS3ST6	XM_011522609.2 link	c.196G>T	p.Ala66Ser	missense_variant	Exon 2 of 2		XP_011520911.1
HS3ST6	XM_047434487.1 link	c.196G>T	p.Ala66Ser	missense_variant	Exon 2 of 2		XP_047290443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HS3ST6	ENST00000454677.3 link	c.616G>T	p.Ala206Ser	missense_variant	Exon 2 of 2	1	NM_001009606.4	ENSP00000416741.3		Q96QI5

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000734

AC:

131

AN:

178384

Hom.:

AF XY:

0.000871

AC XY:

AN XY:

95284

show subpopulations

Gnomad AFR exome

AF:

0.000144

Gnomad AMR exome

AF:

0.0000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000292

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.000737

GnomAD4 exome

AF:

0.000989

AC:

1364

AN:

1379440

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

618

AN XY:

677704

show subpopulations

Gnomad4 AFR exome

AF:

0.0000978

Gnomad4 AMR exome

AF:

0.0000924

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000505

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.000688

GnomAD4 genome

AF:

0.000624

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00129

AC:

ExAC

AF:

0.000793

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>T (p.A175S) alteration is located in exon 2 (coding exon 2) of the HS3ST6 gene. This alteration results from a G to T substitution at nucleotide position 523, causing the alanine (A) at amino acid position 175 to be replaced by a serine (S). 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

Benign

0.075

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.6

DANN

Benign

0.18

DEOGEN2

Benign

0.043

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.67

M_CAP

Benign

0.0078

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.48

PrimateAI

Uncertain

0.49

REVEL

Benign

0.037

Sift4G

Benign

1.0

Polyphen

0.0060

Vest4

0.046

MVP

0.095

ClinPred

0.0042

GERP RS

2.9

Varity_R

0.029

gMVP

0.23

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