16-25692845-C-T

Position:

• chr16-25692845-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006040.3(HS3ST4):​c.428C>T​(p.Pro143Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000925 in 1,297,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: HS3ST4 NM_006040.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.660

Genes affected

HS3ST4 (HGNC:5200): (heparan sulfate-glucosamine 3-sulfotransferase 4) This gene encodes the enzyme heparan sulfate D-glucosaminyl 3-O-sulfotransferase 4. This enzyme generates 3-O-sulfated glucosaminyl residues in heparan sulfate. Cell surface heparan sulfate is used as a receptor by herpes simplex virus type 1 (HSV-1), and expression of this gene is thought to play a role in HSV-1 pathogenesis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12451154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HS3ST4	NM_006040.3	c.428C>T	p.Pro143Leu	missense_variant	1/2	ENST00000331351.6	NP_006031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HS3ST4	ENST00000331351.6	c.428C>T	p.Pro143Leu	missense_variant	1/2	1	NM_006040.3	ENSP00000330606.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000925 AC: 12 AN: 1297454 Hom.: 0 Cov.: 34 AF XY: 0.00000633 AC XY: 4 AN XY: 632262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000966

Gnomad4 OTH exome AF: 0.0000373

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.428C>T (p.P143L) alteration is located in exon 1 (coding exon 1) of the HS3ST4 gene. This alteration results from a C to T substitution at nucleotide position 428, causing the proline (P) at amino acid position 143 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	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.053
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.25	B
Vest4		0.10
MutPred		0.34		Loss of glycosylation at P143 (P = 0.0704);
MVP		0.13
MPC		1.6
ClinPred		0.45	T
GERP RS		2.9
Varity_R		0.10
gMVP		0.25

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: rs1170468033; hg19: chr16-25704166;