5-150540266-TG-TGG

Position:

• chr5-150540266-TG-TGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001543.5(NDST1):​c.1749+8dup variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,599,600 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: NDST1 NM_001543.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.169

Genes affected

NDST1 (HGNC:7680): (N-deacetylase and N-sulfotransferase 1) This gene encodes a member of the heparan sulfate/heparin GlcNAc N-deacetylase/ N-sulfotransferase family. The encoded enzyme is a type II transmembrane protein that resides in the Golgi apparatus. The encoded protein catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to nitrogen of glucosamine in heparan sulfate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 5-150540266-T-TG is Benign according to our data. Variant chr5-150540266-T-TG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435952.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDST1	NM_001543.5	c.1749+8dup		splice_region_variant, intron_variant		ENST00000261797.7
NDST1	NM_001301063.2	c.1749+8dup		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDST1	ENST00000261797.7	c.1749+8dup		splice_region_variant, intron_variant		1	NM_001543.5	P1
NDST1	ENST00000523767.5	c.1749+8dup		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00119 AC: 285 AN: 239542 Hom.: 1 AF XY: 0.00145 AC XY: 187 AN XY: 129148

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000559

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.000854

GnomAD4 exome AF: 0.00209 AC: 3023 AN: 1447458 Hom.: 7 Cov.: 34 AF XY: 0.00213 AC XY: 1532 AN XY: 717956

Gnomad4 AFR exome AF: 0.000391

Gnomad4 AMR exome AF: 0.000407

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.0000946

Gnomad4 NFE exome AF: 0.00246

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74402

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.00111

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 14, 2016

- -

NDST1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs528143978; hg19: chr5-149919828;