Genetic Variant HS6ST3:p.Arg42Leu (chr13-96090987-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_153456.4(HS6ST3):c.125G>T(p.Arg42Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000834 in 1,198,786 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 (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

HS6ST3
NM_153456.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27948532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS6ST3	NM_153456.4 link	c.125G>T	p.Arg42Leu	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.125G>T	p.Arg42Leu	missense_variant	Exon 1 of 2	1	NM_153456.4	ENSP00000365895.2		Q8IZP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.34e-7

AC:

AN:

1198786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

585838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25196

American (AMR)

AF:

0.00

AC:

AN:

21458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16760

East Asian (EAS)

AF:

0.00

AC:

AN:

28916

South Asian (SAS)

AF:

0.00

AC:

AN:

40276

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4750

European-Non Finnish (NFE)

AF:

0.00000103

AC:

AN:

974320

Other (OTH)

AF:

0.00

AC:

AN:

46886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.125G>T (p.R42L) alteration is located in exon 1 (coding exon 1) of the HS6ST3 gene. This alteration results from a G to T substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a leucine (L). 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

0.11

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0057

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.81

PhyloP100

4.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.73

REVEL

Benign

0.25

Sift

Uncertain

0.012

Sift4G

Uncertain

0.026

Polyphen

0.0010

Vest4

0.42

MutPred

0.34

Gain of catalytic residue at Q40 (P = 0);

MVP

0.11

MPC

0.66

ClinPred

0.70

GERP RS

3.5

Varity_R

0.26

gMVP

0.29

Mutation Taster

=77/23

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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13-96090987-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over