Genetic Variant HS3ST6:p.Val223Ile (chr16-1911952-C-T) – 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.667G>A(p.Val223Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,578,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HS3ST6
NM_001009606.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

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=0.024767041).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS3ST6	NM_001009606.4 link	c.667G>A	p.Val223Ile	missense_variant	Exon 2 of 2	ENST00000454677.3	NP_001009606.3	Q96QI5
HS3ST6	XM_011522608.3 link	c.292G>A	p.Val98Ile	missense_variant	Exon 2 of 2		XP_011520910.1
HS3ST6	XM_011522609.2 link	c.247G>A	p.Val83Ile	missense_variant	Exon 2 of 2		XP_011520911.1
HS3ST6	XM_047434487.1 link	c.247G>A	p.Val83Ile	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.667G>A	p.Val223Ile	missense_variant	Exon 2 of 2	1	NM_001009606.4	ENSP00000416741.3		Q96QI5

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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

GnomAD3 exomes

AF:

0.000120

AC:

AN:

217110

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

116824

show subpopulations

Gnomad AFR exome

AF:

0.000202

Gnomad AMR exome

AF:

0.000652

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000173

Gnomad SAS 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:

0.0000231

AC:

AN:

1426284

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

705318

show subpopulations

Gnomad4 AFR exome

AF:

0.000275

Gnomad4 AMR exome

AF:

0.000510

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.15e-7

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.000151

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000581

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574G>A (p.V192I) alteration is located in exon 2 (coding exon 2) of the HS3ST6 gene. This alteration results from a G to A substitution at nucleotide position 574, causing the valine (V) at amino acid position 192 to be replaced by an isoleucine (I). 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

0.090

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.54

DEOGEN2

Benign

0.080

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.77

M_CAP

Benign

0.0095

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.030

PrimateAI

Uncertain

0.62

REVEL

Benign

0.045

Sift4G

Benign

1.0

Polyphen

0.085

Vest4

0.063

MVP

0.030

ClinPred

0.014

GERP RS

3.9

Varity_R

0.029

gMVP

0.22

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