rs606231458

chr5-150542919-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001543.5(NDST1):c.1918T>C(p.Phe640Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F640S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDST1 NM_001543.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.97

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Heparan sulfate N-sulfotransferase 1 (size 283) in uniprot entity NDST1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001543.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NDST1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 5-150542919-T-C is Pathogenic according to our data. Variant chr5-150542919-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161411.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDST1	NM_001543.5	c.1918T>C	p.Phe640Leu	missense_variant	10/15	ENST00000261797.7
NDST1	NM_001301063.2	c.1918T>C	p.Phe640Leu	missense_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDST1	ENST00000261797.7	c.1918T>C	p.Phe640Leu	missense_variant	10/15	1	NM_001543.5	P1
NDST1	ENST00000523767.5	c.1918T>C	p.Phe640Leu	missense_variant	10/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 46 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2020	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM1,PM2,PM3_Supporting,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.76	P;P
Vest4		0.79
MutPred		0.50		Loss of glycosylation at S637 (P = 0.1057);Loss of glycosylation at S637 (P = 0.1057);
MVP		0.93
MPC		0.84
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.74

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: rs606231458; hg19: chr5-149922481;