Genetic Variant HS6ST3:p.Ala50Val (chr13-96091011-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_153456.4(HS6ST3):c.149C>T(p.Ala50Val) variant causes a missense change. The variant allele was found at a frequency of 0.00023 in 1,284,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A50T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

HS6ST3
NM_153456.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Publications

0 publications found

Variant links:

Genes affected

HS6ST3 (HGNC:19134): (heparan sulfate 6-O-sulfotransferase 3) Heparan sulfate (HS) sulfotransferases, such as HS6ST3, modify HS to generate structures required for interactions between HS and a variety of proteins. These interactions are implicated in proliferation and differentiation, adhesion, migration, inflammation, blood coagulation, and other diverse processes (Habuchi et al., 2000 [PubMed 10644753]).[supplied by OMIM, Mar 2008]

HS6ST3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23632851).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS6ST3	NM_153456.4 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	ENST00000376705.4	NP_703157.2	Q8IZP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HS6ST3	ENST00000376705.4 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	1	NM_153456.4	ENSP00000365895.2		Q8IZP7

Frequencies

GnomAD3 genomes

AF:

0.0000932

AC:

AN:

150198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

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:

0.000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000169

AC:

AN:

65196

AF XY:

0.000276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000190

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000249

AC:

282

AN:

1134090

Hom.:

Cov.:

AF XY:

0.000236

AC XY:

129

AN XY:

545630

show subpopulations

African (AFR)

AF:

0.0000831

AC:

AN:

24066

American (AMR)

AF:

0.000294

AC:

AN:

13594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14094

East Asian (EAS)

AF:

0.00

AC:

AN:

28144

South Asian (SAS)

AF:

0.00

AC:

AN:

27314

European-Finnish (FIN)

AF:

0.0000301

AC:

AN:

33266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4510

European-Non Finnish (NFE)

AF:

0.000283

AC:

267

AN:

944454

Other (OTH)

AF:

0.000179

AC:

AN:

44648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000932

AC:

AN:

150198

Hom.:

Cov.:

AF XY:

0.0000955

AC XY:

AN XY:

73314

show subpopulations

African (AFR)

AF:

0.0000729

AC:

AN:

41144

American (AMR)

AF:

0.0000662

AC:

AN:

15106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5012

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67496

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000987

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.149C>T (p.A50V) alteration is located in exon 1 (coding exon 1) of the HS6ST3 gene. This alteration results from a C to T substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by a valine (V). 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

0.097

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0084

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.071

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.24

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.81

PhyloP100

4.7

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.41

REVEL

Benign

0.27

Sift

Uncertain

0.0040

Sift4G

Benign

0.11

Polyphen

0.61

Vest4

0.31

MutPred

0.18

Gain of catalytic residue at P48 (P = 0.0016);

MVP

0.40

MPC

0.53

ClinPred

0.11

GERP RS

3.5

Varity_R

0.17

gMVP

0.33

Mutation Taster

=81/19

polymorphism

(source)

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

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13-96091011-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over