16-25692422-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006040.3(HS3ST4):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000492 in 1,055,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000083 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

HS3ST4
NM_006040.3 missense

Scores

3
2
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.915
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.16285983).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HS3ST4NM_006040.3 linkc.5C>T p.Ala2Val missense_variant Exon 1 of 2 ENST00000331351.6 NP_006031.2 Q9Y661

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HS3ST4ENST00000331351.6 linkc.5C>T p.Ala2Val missense_variant Exon 1 of 2 1 NM_006040.3 ENSP00000330606.5 Q9Y661

Frequencies

GnomAD3 genomes
AF:
0.0000826
AC:
12
AN:
145352
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000745
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000137
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000224
AC:
1
AN:
4472
Hom.:
0
AF XY:
0.000374
AC XY:
1
AN XY:
2674
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000321
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000439
AC:
40
AN:
910640
Hom.:
0
Cov.:
14
AF XY:
0.0000459
AC XY:
20
AN XY:
435456
show subpopulations
Gnomad4 AFR exome
AF:
0.0000560
Gnomad4 AMR exome
AF:
0.000182
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:
0.0000469
Gnomad4 OTH exome
AF:
0.0000296
GnomAD4 genome
AF:
0.0000826
AC:
12
AN:
145352
Hom.:
0
Cov.:
31
AF XY:
0.0000566
AC XY:
4
AN XY:
70724
show subpopulations
Gnomad4 AFR
AF:
0.0000745
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000137
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000843
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 09, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5C>T (p.A2V) 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 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). 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
Uncertain
0.38
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
22
DANN
Benign
0.95
DEOGEN2
Benign
0.00033
T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.39
T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-0.21
N
REVEL
Benign
0.055
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.21
B
Vest4
0.17
MutPred
0.25
Loss of relative solvent accessibility (P = 0.0404);
MVP
0.043
MPC
1.6
ClinPred
0.16
T
GERP RS
1.9
Varity_R
0.11
gMVP
0.38

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.

Other links and lift over

dbSNP: rs967063661; hg19: chr16-25703743; API