dbSNP rs1211171924: HS6ST3:p.Gly77Arg (chr13-96091091-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153456.4(HS6ST3):c.229G>A(p.Gly77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000868 in 1,152,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.7e-7 ( 0 hom. )

Consequence

HS6ST3
NM_153456.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.687

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1400362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS6ST3	NM_153456.4 link	c.229G>A	p.Gly77Arg	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.229G>A	p.Gly77Arg	missense_variant	Exon 1 of 2	1	NM_153456.4	ENSP00000365895.2		Q8IZP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.68e-7

AC:

AN:

1152296

Hom.:

Cov.:

AF XY:

0.00000181

AC XY:

AN XY:

553240

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23374

American (AMR)

AF:

0.00

AC:

AN:

9292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15584

East Asian (EAS)

AF:

0.00

AC:

AN:

27208

South Asian (SAS)

AF:

0.0000279

AC:

AN:

35882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3362

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

962846

Other (OTH)

AF:

0.00

AC:

AN:

46528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.69

PhyloP100

0.69

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.40

REVEL

Benign

0.12

Sift

Benign

0.16

Sift4G

Benign

0.13

Polyphen

0.0010

Vest4

0.23

MutPred

0.30

Gain of catalytic residue at P72 (P = 5e-04);

MVP

0.068

MPC

0.63

ClinPred

0.053

GERP RS

2.1

Varity_R

0.061

gMVP

0.31

Mutation Taster

=88/12

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over