chr16-25692652-C-A

Variant names:

• chr16-25692652-C-A
• rs547472104
• NM_006040.3:c.235C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006040.3(HS3ST4):​c.235C>A​(p.Pro79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 149,188 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. P79L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HS3ST4 NM_006040.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.578
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040137976).

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.235C>A	p.Pro79Thr	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.235C>A	p.Pro79Thr	missense	Exon 1 of 2	ENSP00000330606.5	Q9Y661
	ENSG00000310159	ENST00000847723.1		n.50G>T		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000310159	ENST00000847724.1		n.50G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 149086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.32e-7 AC: 1 AN: 1202100 Hom.: 0 Cov.: 31 AF XY: 0.00000169 AC XY: 1 AN XY: 589986

⚠️ 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: 24872

American (AMR) AF: 0.00 AC: 0 AN: 22664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19216

East Asian (EAS) AF: 0.00 AC: 0 AN: 24744

South Asian (SAS) AF: 0.0000180 AC: 1 AN: 55574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 976022

Other (OTH) AF: 0.00 AC: 0 AN: 47334

⚠️ 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 AF: 0.00000670 AC: 1 AN: 149188 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 72784

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

African (AFR) AF: 0.0000243 AC: 1 AN: 41184

American (AMR) AF: 0.00 AC: 0 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66880

Other (OTH) AF: 0.00 AC: 0 AN: 2076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.58
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.036
Sift	Benign	0.28	T
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.21
MutPred		0.21		Gain of phosphorylation at P79 (P = 0.0033)
MVP		0.32
MPC		1.7
ClinPred		0.059	T
GERP RS		2.2
Varity_R		0.10
gMVP		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

Other links and lift over

dbSNP: rs547472104; hg19: chr16-25703973;