5-150540266-TG-TGG

Variant names:

• chr5-150540266-T-TG
• rs528143978
• NM_001543.5:c.1749+8dupG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001543.5(NDST1):​c.1749+8dupG variant causes a 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. 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.169
• Publications: 0 publications found

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]

NDST1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 46

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 435952.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001543.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDST1	NM_001543.5	MANE Select	c.1749+8dupG		intron	N/A	NP_001534.1
	NDST1	NM_001301063.2		c.1749+8dupG		intron	N/A	NP_001287992.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDST1	ENST00000261797.7	TSL:1 MANE Select	c.1749+2_1749+3insG		splice_region intron	N/A	ENSP00000261797.6
	NDST1	ENST00000523767.5	TSL:2	c.1749+2_1749+3insG		splice_region intron	N/A	ENSP00000428604.1

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

GnomAD2 exomes AF: 0.00119 AC: 285 AN: 239542 AF XY: 0.00145

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 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

African (AFR) AF: 0.000391 AC: 13 AN: 33284

American (AMR) AF: 0.000407 AC: 18 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25206

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39504

South Asian (SAS) AF: 0.00194 AC: 164 AN: 84490

European-Finnish (FIN) AF: 0.0000946 AC: 5 AN: 52834

Middle Eastern (MID) AF: 0.000605 AC: 3 AN: 4958

European-Non Finnish (NFE) AF: 0.00246 AC: 2709 AN: 1103184

Other (OTH) AF: 0.00181 AC: 108 AN: 59734

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

African (AFR) AF: 0.000217 AC: 9 AN: 41524

American (AMR) AF: 0.000851 AC: 13 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 67972

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Intellectual disability (1)
-	-	1	NDST1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs528143978; hg19: chr5-149919828;