chr4-11406961-T-C

Position:

• chr4-11406961-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005114.4(HS3ST1):​c.-108-6848A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 152,000 control chromosomes in the GnomAD database, including 5,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (★).

• Frequency: Genomes: 𝑓 0.27 (5581 hom., cov: 32)
• Consequence: HS3ST1 NM_005114.4 intron
• Clinical Significance: risk factor criteria provided, single submitter O:1
• Conservation: PhyloP100: -1.49

Genes affected

HS3ST1 (HGNC:5194): (heparan sulfate-glucosamine 3-sulfotransferase 1) Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It possesses both heparan sulfate glucosaminyl 3-O-sulfotransferase activity, anticoagulant heparan sulfate conversion activity, and is a rate limiting enzyme for synthesis of anticoagulant heparan. This enzyme is an intraluminal Golgi resident protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HS3ST1	NM_005114.4	c.-108-6848A>G		intron_variant		ENST00000002596.6	NP_005105.1
HS3ST1	XM_011513913.4	c.-108-6848A>G		intron_variant			XP_011512215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HS3ST1	ENST00000002596.6	c.-108-6848A>G		intron_variant		1	NM_005114.4	ENSP00000002596	P1
HS3ST1	ENST00000510712.1	c.-108-6848A>G		intron_variant		2		ENSP00000422629
HS3ST1	ENST00000514690.5	c.-108-6848A>G		intron_variant		3		ENSP00000425673

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40954 AN: 151882 Hom.: 5575 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.270 AC: 40980 AN: 152000 Hom.: 5581 Cov.: 32 AF XY: 0.271 AC XY: 20153 AN XY: 74288

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.254

Alfa AF: 0.256 Hom.: 5198

Bravo AF: 0.262

Asia WGS AF: 0.299 AC: 1040 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arteriosclerosis disorder;C1956346:Coronary artery disorder Other:1

risk factor, criteria provided, single submitter

clinical testing;in vitro;in vivo;research

Shworak lab, George Washington University

May 11, 2014

- Within 2144 cardiac coronary catheterization patients, the minor allele homozygous genotype associated strongly (adjusted OR of 1.77 [1.29-2.43], P = 0.0004) and independently to the severity of coronary artery disease, which was angiographically assessed by a modified SYNTAX score converted to a four-level scale. The minor allele homozygous phenotype also associated strongly (adjusted OR of 1.69 [1.11-2.59], P = 0.015) and independently to Any ASCVD event. Bioinformatic analysis suggests the variant is in a transcriptional control region.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.32

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

Other links and lift over

dbSNP: rs16881446; hg19: chr4-11408585;