16-25692464-C-A

Variant names:

• chr16-25692464-C-A
• rs1051885767
• NM_006040.3:c.47C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006040.3(HS3ST4):​c.47C>A​(p.Pro16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000827 in 1,208,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P16L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: HS3ST4 NM_006040.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

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]

ENSG00000310159 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16046402).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006040.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS3ST4	NM_006040.3	MANE Select	c.47C>A	p.Pro16His	missense	Exon 1 of 2	NP_006031.2	Q9Y661

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS3ST4	ENST00000331351.6	TSL:1 MANE Select	c.47C>A	p.Pro16His	missense	Exon 1 of 2	ENSP00000330606.5	Q9Y661
	ENSG00000310159	ENST00000847723.1		n.143+95G>T		intron	N/A
	ENSG00000310159	ENST00000847724.1		n.143+95G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.27e-7 AC: 1 AN: 1208570 Hom.: 0 Cov.: 30 AF XY: 0.00000168 AC XY: 1 AN XY: 594272

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24496

American (AMR) AF: 0.00 AC: 0 AN: 23400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19186

East Asian (EAS) AF: 0.00 AC: 0 AN: 24022

South Asian (SAS) AF: 0.00 AC: 0 AN: 59580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4698

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 974476

Other (OTH) AF: 0.00 AC: 0 AN: 47160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.00067	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.085
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.24
MutPred		0.18		Loss of glycosylation at P16 (P = 9e-04)
MVP		0.12
MPC		1.8
ClinPred		0.30	T
GERP RS		1.3
Varity_R		0.15
gMVP		0.22

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

Other links and lift over

dbSNP: rs1051885767; hg19: chr16-25703785;