rs1449421544

Variant names:

• chr13-96091107-C-G
• rs1449421544
• NM_153456.4:c.245C>G

Variant summary

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

The NM_153456.4(HS6ST3):​c.245C>G​(p.Pro82Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,417,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: HS6ST3 NM_153456.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.786
• Publications: 0 publications found

Genes affected

HS6ST3 (HGNC:19134): (heparan sulfate 6-O-sulfotransferase 3) Heparan sulfate (HS) sulfotransferases, such as HS6ST3, modify HS to generate structures required for interactions between HS and a variety of proteins. These interactions are implicated in proliferation and differentiation, adhesion, migration, inflammation, blood coagulation, and other diverse processes (Habuchi et al., 2000 [PubMed 10644753]).[supplied by OMIM, Mar 2008]

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=0.14421931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS6ST3	NM_153456.4	c.245C>G	p.Pro82Arg	missense_variant	Exon 1 of 2	ENST00000376705.4	NP_703157.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HS6ST3	ENST00000376705.4	c.245C>G	p.Pro82Arg	missense_variant	Exon 1 of 2	1	NM_153456.4	ENSP00000365895.2

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 149926 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

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

GnomAD2 exomes AF: 0.0000233 AC: 1 AN: 42990 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1267194 Hom.: 0 Cov.: 32 AF XY: 0.00000324 AC XY: 2 AN XY: 616348

African (AFR) AF: 0.00 AC: 0 AN: 26016

American (AMR) AF: 0.0000529 AC: 1 AN: 18886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18636

East Asian (EAS) AF: 0.00 AC: 0 AN: 30540

South Asian (SAS) AF: 0.00 AC: 0 AN: 59134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34216

Middle Eastern (MID) AF: 0.000259 AC: 1 AN: 3854

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1023882

Other (OTH) AF: 0.0000192 AC: 1 AN: 52030

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 149926 Hom.: 0 Cov.: 30 AF XY: 0.0000137 AC XY: 1 AN XY: 73160

African (AFR) AF: 0.00 AC: 0 AN: 41052

American (AMR) AF: 0.000133 AC: 2 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4932

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67302

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245C>G (p.P82R) alteration is located in exon 1 (coding exon 1) of the HS6ST3 gene. This alteration results from a C to G substitution at nucleotide position 245, causing the proline (P) at amino acid position 82 to be replaced by an arginine (R). 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	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.8
DANN	Benign	0.81
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.79
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.46	N
REVEL	Benign	0.041
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.25	T
Polyphen		0.12	B
Vest4		0.18
MutPred		0.29		Gain of catalytic residue at P78 (P = 8e-04);
MVP		0.068
MPC		0.56
ClinPred		0.047	T
GERP RS		1.4
Varity_R		0.045
gMVP		0.26
Mutation Taster		=98/2	polymorphism

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: rs1449421544; hg19: chr13-96743361;