Genetic Variant NM_001009606.4:c.946C>G (chr16-1911673-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001009606.4(HS3ST6):c.946C>G(p.Leu316Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,609,752 control chromosomes in the GnomAD database, including 254,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.57 ( 24981 hom., cov: 33)

Exomes 𝑓: 0.56 ( 229931 hom. )

Consequence

HS3ST6
NM_001009606.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.25

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.9493526E-6).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS3ST6	NM_001009606.4 link	c.946C>G	p.Leu316Val	missense_variant	Exon 2 of 2	ENST00000454677.3	NP_001009606.3	Q96QI5
HS3ST6	XM_011522608.3 link	c.571C>G	p.Leu191Val	missense_variant	Exon 2 of 2		XP_011520910.1
HS3ST6	XM_011522609.2 link	c.526C>G	p.Leu176Val	missense_variant	Exon 2 of 2		XP_011520911.1
HS3ST6	XM_047434487.1 link	c.526C>G	p.Leu176Val	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.946C>G	p.Leu316Val	missense_variant	Exon 2 of 2	1	NM_001009606.4	ENSP00000416741.3		Q96QI5

Frequencies

GnomAD3 genomes

AF:

0.571

AC:

86779

AN:

151946

Hom.:

24933

Cov.:

show subpopulations

Gnomad AFR

AF:

0.600

Gnomad AMI

AF:

0.536

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.659

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.550

Gnomad OTH

AF:

0.554

GnomAD3 exomes

AF:

0.561

AC:

133920

AN:

238854

Hom.:

38400

AF XY:

0.573

AC XY:

74724

AN XY:

130310

show subpopulations

Gnomad AFR exome

AF:

0.600

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.588

Gnomad EAS exome

AF:

0.508

Gnomad SAS exome

AF:

0.712

Gnomad FIN exome

AF:

0.638

Gnomad NFE exome

AF:

0.553

Gnomad OTH exome

AF:

0.569

GnomAD4 exome

AF:

0.559

AC:

814244

AN:

1457688

Hom.:

229931

Cov.:

AF XY:

0.564

AC XY:

409148

AN XY:

724912

show subpopulations

Gnomad4 AFR exome

AF:

0.605

Gnomad4 AMR exome

AF:

0.414

Gnomad4 ASJ exome

AF:

0.588

Gnomad4 EAS exome

AF:

0.560

Gnomad4 SAS exome

AF:

0.709

Gnomad4 FIN exome

AF:

0.637

Gnomad4 NFE exome

AF:

0.546

Gnomad4 OTH exome

AF:

0.569

GnomAD4 genome

AF:

0.571

AC:

86874

AN:

152064

Hom.:

24981

Cov.:

AF XY:

0.577

AC XY:

42888

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.601

Gnomad4 AMR

AF:

0.500

Gnomad4 ASJ

AF:

0.586

Gnomad4 EAS

AF:

0.518

Gnomad4 SAS

AF:

0.708

Gnomad4 FIN

AF:

0.659

Gnomad4 NFE

AF:

0.550

Gnomad4 OTH

AF:

0.558

Alfa

AF:

0.527

Hom.:

6048

Bravo

AF:

0.551

TwinsUK

AF:

0.541

AC:

2007

ALSPAC

AF:

0.551

AC:

2123

ESP6500AA

AF:

0.595

AC:

2516

ESP6500EA

AF:

0.545

AC:

4601

ExAC

AF:

0.562

AC:

67615

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Angioedema, hereditary, 8

Uncertain:1

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.53

DANN

Benign

0.090

DEOGEN2

Benign

0.055

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.092

MetaRNN

Benign

0.0000029

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.9

PrimateAI

Uncertain

0.52

REVEL

Benign

0.22

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.044

ClinPred

0.0075

GERP RS

1.8

Varity_R

0.041

gMVP

0.44

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