13-96091080-C-T

Variant names:

• chr13-96091080-C-T
• rs1219432944
• NM_153456.4:c.218C>T

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.218C>T​(p.Pro73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000232 in 1,294,284 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: HS6ST3 NM_153456.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103
• 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=0.15670851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HS6ST3	NM_153456.4	c.218C>T	p.Pro73Leu	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.218C>T	p.Pro73Leu	missense_variant	Exon 1 of 2	1	NM_153456.4	ENSP00000365895.2

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149664 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000488

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 AF: 8.74e-7 AC: 1 AN: 1144620 Hom.: 0 Cov.: 32 AF XY: 0.00000182 AC XY: 1 AN XY: 548856

⚠️ 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: 23246

American (AMR) AF: 0.00 AC: 0 AN: 8986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15356

East Asian (EAS) AF: 0.00 AC: 0 AN: 27108

South Asian (SAS) AF: 0.00 AC: 0 AN: 34040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3448

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 958560

Other (OTH) AF: 0.00 AC: 0 AN: 46204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149664 Hom.: 0 Cov.: 30 AF XY: 0.0000274 AC XY: 2 AN XY: 73062

African (AFR) AF: 0.0000488 AC: 2 AN: 40964

American (AMR) AF: 0.00 AC: 0 AN: 15042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9956

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67248

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.218C>T (p.P73L) alteration is located in exon 1 (coding exon 1) of the HS6ST3 gene. This alteration results from a C to T substitution at nucleotide position 218, causing the proline (P) at amino acid position 73 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	0.10
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.25
MutPred		0.32		Gain of catalytic residue at P74 (P = 8e-04);
MVP		0.24
MPC		0.54
ClinPred		0.17	T
GERP RS		3.0
Varity_R		0.096
gMVP		0.34
Mutation Taster		=86/14	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: rs1219432944; hg19: chr13-96743334;