5-150521433-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001543.5(NDST1):c.179C>T(p.Pro60Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,612,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (1 hom.)
• Consequence: NDST1 NM_001543.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NDST1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15785232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDST1	NM_001543.5	c.179C>T	p.Pro60Leu	missense_variant	2/15	ENST00000261797.7
NDST1	NM_001301063.2	c.179C>T	p.Pro60Leu	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDST1	ENST00000261797.7	c.179C>T	p.Pro60Leu	missense_variant	2/15	1	NM_001543.5	P1
NDST1	ENST00000523767.5	c.179C>T	p.Pro60Leu	missense_variant	2/14	2
NDST1	ENST00000519157.1	c.179C>T	p.Pro60Leu	missense_variant	2/2	5
NDST1	ENST00000522491.1	c.179C>T	p.Pro60Leu	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000566 AC: 14 AN: 247418 Hom.: 0 AF XY: 0.0000745 AC XY: 10 AN XY: 134244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1460774 Hom.: 1 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 726746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

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

Mar 06, 2023

The c.179C>T (p.P60L) alteration is located in exon 2 (coding exon 1) of the NDST1 gene. This alteration results from a C to T substitution at nucleotide position 179, causing the proline (P) at amino acid position 60 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	0.064
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Benign	0.87
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.78	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.021, 0.0070	.;.;B;B
Vest4		0.29, 0.28
MutPred		0.28		Loss of catalytic residue at P59 (P = 0.0116);Loss of catalytic residue at P59 (P = 0.0116);Loss of catalytic residue at P59 (P = 0.0116);Loss of catalytic residue at P59 (P = 0.0116);
MVP		0.32
MPC		0.75
ClinPred		0.072	T
GERP RS		5.1
Varity_R		0.10
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs775828301; hg19: chr5-149900995;