rs186262357

chr5-150549674-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001543.5(NDST1):c.2317-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000773 in 1,603,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: NDST1 NM_001543.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008232
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.298

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 5-150549674-C-G is Benign according to our data. Variant chr5-150549674-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435955.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDST1	NM_001543.5	c.2317-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261797.7
NDST1	NM_001301063.2	c.2146-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDST1	ENST00000261797.7	c.2317-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001543.5	P1
NDST1	ENST00000523767.5	c.2146-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 250790 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000689 AC: 100 AN: 1451136 Hom.: 0 Cov.: 29 AF XY: 0.0000623 AC XY: 45 AN XY: 722588

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00179

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000726

Gnomad4 OTH exome AF: 0.0000832

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000185

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 22, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	2.8
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.0040
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

LitVar

Other links and lift over

dbSNP: rs186262357; hg19: chr5-149929236; COSMIC: COSV55791866; COSMIC: COSV55791866;