chr1-87073135-C-T

Position:

• chr1-87073135-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012262.4(HS2ST1):​c.326C>T​(p.Thr109Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HS2ST1 NM_012262.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

Genes affected

HS2ST1 (HGNC:5193): (heparan sulfate 2-O-sulfotransferase 1) Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. This gene encodes a member of the heparan sulfate biosynthetic enzyme family that transfers sulfate to the 2 position of the iduronic acid residue of heparan sulfate. The disruption of this gene resulted in no kidney formation in knockout embryonic mice, indicating that the absence of this enzyme may interfere with the signaling required for kidney formation. Two alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Aug 2008]

ENSG00000267561 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HS2ST1	NM_012262.4	c.326C>T	p.Thr109Ile	missense_variant	2/7	ENST00000370550.10	NP_036394.1
HS2ST1	NM_001134492.2	c.326C>T	p.Thr109Ile	missense_variant	2/5		NP_001127964.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HS2ST1	ENST00000370550.10	c.326C>T	p.Thr109Ile	missense_variant	2/7	1	NM_012262.4	ENSP00000359581.4
ENSG00000267561	ENST00000370548.3	c.248C>T	p.Thr83Ile	missense_variant	2/8	2		ENSP00000359579.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.326C>T (p.T109I) alteration is located in exon 2 (coding exon 2) of the HS2ST1 gene. This alteration results from a C to T substitution at nucleotide position 326, causing the threonine (T) at amino acid position 109 to be replaced by an isoleucine (I). 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	0.54
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T;T;.
Eigen	Benign	0.034
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.86	L;L;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.77	N;N;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.55	T;T;.;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.49	.;P;.;.
Vest4		0.88
MutPred		0.66		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;.;
MVP		0.72
MPC		0.53, 0.40
ClinPred		0.86	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-87538818;