Variant X-43949833-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Moderate

The NM_000266.4(NDP):c.368T>A(p.Ile123Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000933 in 1,071,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.3e-7 ( 0 hom. 1 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.91

Variant links:

Genes affected

NDP (HGNC:7678): (norrin cystine knot growth factor NDP) This gene encodes a secreted protein with a cystein-knot motif that activates the Wnt/beta-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. Mutations in this gene result in Norrie disease and X-linked exudative vitreoretinopathy. [provided by RefSeq, Feb 2009]

NDP links:

NDP-AS1 (HGNC:40395): (NDP antisense RNA 1)

NDP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1

Transcript NM_000266.4 (NDP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a disulfide_bond (size 61) in uniprot entity NDP_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_000266.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant X-43949833-A-T is Pathogenic according to our data. Variant chrX-43949833-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2737210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.368T>A	p.Ile123Asn	missense_variant	3/3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.102A>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NDP	ENST00000642620.1 link	c.368T>A	p.Ile123Asn	missense_variant	3/3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.368T>A	p.Ile123Asn	missense_variant	4/4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.102A>T		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000470584.1 link	n.412T>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.33e-7

AC:

AN:

1071578

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349288

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:

0.00000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 123 of the NDP protein (p.Ile123Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Norrie disease (PMID: 7627181; Invitae). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDP protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;D;D

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;.;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

0.97

L;L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.1

.;D;.

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;D

Vest4

0.93

MutPred

0.84

Gain of disorder (P = 0.0014);Gain of disorder (P = 0.0014);Gain of disorder (P = 0.0014);

MVP

0.98

MPC

1.9

ClinPred

1.0

GERP RS

6.0

Varity_R

0.98

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over