chrX-43949840-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000266.4(NDP):c.361C>T(p.Arg121Trp) variant causes a missense change. 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. R121L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.11

Publications

12 publications found

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 was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000266.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-43949839-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3249058.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Norrie disease, exudative vitreoretinopathy 2, X-linked, exudative vitreoretinopathy, persistent hyperplastic primary vitreous.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant X-43949840-G-A is Pathogenic according to our data. Variant chrX-43949840-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.109G>A		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDP	ENST00000642620.1 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 4 of 4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.109G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1 link	n.405C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1073891

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

350053

African (AFR)

AF:

0.00

AC:

AN:

25851

American (AMR)

AF:

0.00

AC:

AN:

31274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18894

East Asian (EAS)

AF:

0.00

AC:

AN:

28809

South Asian (SAS)

AF:

0.00

AC:

AN:

51035

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4112

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829794

Other (OTH)

AF:

0.00

AC:

AN:

45224

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the NDP protein (p.Arg121Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with exudative vitreoretinopathy (PMID: 7558002, 7795608, 8832723, 17296899, 20491809). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10688). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects NDP function (PMID: 26158506). For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2015

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R121W variant in the NDP gene has been reported previously in association with X-linked familial exudative vitreoretinopathy (Meindl et al., 1995; Pelcastre et al., 2010; Fuchs et al., 1995; Wu et al., 2007). The R121W variant was not observed in approximately 6,488 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R121W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information R121W is interpreted to be a likely pathogenic variant. -

Exudative vitreoretinopathy 2, X-linked

Pathogenic:1

Jan 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2012

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrophia bulborum hereditaria

Pathogenic:1

Jul 12, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used to clasify this variant: PS4_MOD, PP3_MOD, PM2_SUP, PP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

.;.;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

0.97

L;L;L

PhyloP100

6.1

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.3

.;D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;D

Vest4

0.85

MutPred

0.90

Loss of disorder (P = 0.0027);Loss of disorder (P = 0.0027);Loss of disorder (P = 0.0027);

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

6.0

Varity_R

0.93

gMVP

0.96

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over