17-14345059-A-G

Position:

• chr17-14345059-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006041.3(HS3ST3B1):​c.586A>G​(p.Ile196Val) variant causes a missense change. The variant allele was found at a frequency of 0.0243 in 1,587,252 control chromosomes in the GnomAD database, including 566 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 31)
  • Exomes 𝑓: 0.025 (533 hom.)
• Consequence: HS3ST3B1 NM_006041.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01

Genes affected

HS3ST3B1 (HGNC:5198): (heparan sulfate-glucosamine 3-sulfotransferase 3B1) The protein encoded by this gene is a type II integral membrane protein that belongs to the 3-O-sulfotransferases family. These proteins catalyze the addition of sulfate groups at the 3-OH position of glucosamine in heparan sulfate. The substrate specificity of individual members of the family is based on prior modification of the heparan sulfate chain, thus allowing different members of the family to generate binding sites for different proteins on the same heparan sulfate chain. Following treatment with a histone deacetylase inhibitor, expression of this gene is activated in a pancreatic cell line. The increased expression results in promotion of the epithelial-mesenchymal transition. In addition, the modification catalyzed by this protein allows herpes simplex virus membrane fusion and penetration. A very closely related homolog with an almost identical sulfotransferase domain maps less than 1 Mb away. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006789446).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0171 (2599/152150) while in subpopulation SAS AF= 0.0428 (206/4818). AF 95% confidence interval is 0.038. There are 33 homozygotes in gnomad4. There are 1268 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HS3ST3B1	NM_006041.3	c.586A>G	p.Ile196Val	missense_variant	2/2	ENST00000360954.3	NP_006032.1
HS3ST3B1	XM_017025479.3	c.25A>G	p.Ile9Val	missense_variant	2/2		XP_016880968.1
HS3ST3B1	NR_130138.2	n.1024A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HS3ST3B1	ENST00000360954.3	c.586A>G	p.Ile196Val	missense_variant	2/2	1	NM_006041.3	ENSP00000354213	P1
HS3ST3B1	ENST00000466596.5	c.586A>G	p.Ile196Val	missense_variant, NMD_transcript_variant	2/3	2		ENSP00000436078

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2599 AN: 152032 Hom.: 33 Cov.: 31

Gnomad AFR AF: 0.00529

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0202 AC: 4682 AN: 231756 Hom.: 76 AF XY: 0.0222 AC XY: 2764 AN XY: 124636

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.000169

Gnomad SAS exome AF: 0.0405

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0240

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0251 AC: 36020 AN: 1435102 Hom.: 533 Cov.: 32 AF XY: 0.0258 AC XY: 18359 AN XY: 711168

Gnomad4 AFR exome AF: 0.00391

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.0265

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0426

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0171 AC: 2599 AN: 152150 Hom.: 33 Cov.: 31 AF XY: 0.0171 AC XY: 1268 AN XY: 74364

Gnomad4 AFR AF: 0.00527

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0428

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.0242

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0205 Hom.: 7

Bravo AF: 0.0162

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0271 AC: 233

ExAC AF: 0.0217 AC: 2630

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.068
Sift	Benign	0.065	T
Sift4G	Benign	0.099	T
Polyphen		0.040	B
Vest4		0.054
ClinPred		0.035	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.48

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: rs62056073; hg19: chr17-14248376;