rs606231459

Positions:

chr5-150541651-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001543.5(NDST1):c.1831G>A(p.Gly611Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NDST1
NM_001543.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.94

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NDST1. . Gene score misZ 2.9238 (greater than the threshold 3.09). Trascript score misZ 4.3135 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive non-syndromic intellectual disability, intellectual disability, autosomal recessive 46.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 5-150541651-G-A is Pathogenic according to our data. Variant chr5-150541651-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150541651-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDST1	NM_001543.5 linkuse as main transcript	c.1831G>A	p.Gly611Ser	missense_variant	9/15	ENST00000261797.7	NP_001534.1
NDST1	NM_001301063.2 linkuse as main transcript	c.1831G>A	p.Gly611Ser	missense_variant	9/14		NP_001287992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDST1	ENST00000261797.7 linkuse as main transcript	c.1831G>A	p.Gly611Ser	missense_variant	9/15	1	NM_001543.5	ENSP00000261797	P1	P52848-1
NDST1	ENST00000523767.5 linkuse as main transcript	c.1831G>A	p.Gly611Ser	missense_variant	9/14	2		ENSP00000428604		P52848-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250738

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 46

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 11, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2020	Variant summary: NDST1 c.1831G>A (p.Gly611Ser) results in a non-conservative amino acid change located in the Sulfotransferase domain (IPR000863) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250738 control chromosomes (gnomAD). c.1831G>A has been reported in the literature as a homozygous mutation in multiple individuals affected with intellectual disability (e.g. Reuter_2014, Martinez_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 16, 2022	- -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25125150, 31589614, 27870114, 27620904, 35887114) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 23, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NDST1 protein function. ClinVar contains an entry for this variant (Variation ID: 161412). This missense change has been observed in individuals with clinical features of intellectual disability (PMID: 25125150, 27620904; Invitae). This variant is present in population databases (rs606231459, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 611 of the NDST1 protein (p.Gly611Ser). -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NDST1: PM1, PM2, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -

Global developmental delay

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Feb 16, 2022

ACMG criteria used to clasify this variant: PS4, PM1, PM2_SUP, PP3 -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Oct 20, 2022

ACMG categories: PM2,PM3,PP3,PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

4.1

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.96

D;D

Vest4

0.86

MutPred

0.69

Gain of ubiquitination at K614 (P = 0.1084);Gain of ubiquitination at K614 (P = 0.1084);

MVP

0.98

MPC

1.7

ClinPred

0.99

GERP RS

4.0

Varity_R

0.98

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over