rs104894880

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000266.4(NDP):c.181C>T(p.Leu61Phe) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L61I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.38

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 16 ACMG points.

PM1

In a chain Norrin (size 108) in uniprot entity NDP_HUMAN there are 39 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant X-43950020-G-A is Pathogenic according to our data. Variant chrX-43950020-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-43950020-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.181C>T	p.Leu61Phe	missense_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.289G>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.181C>T	p.Leu61Phe	missense_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.181C>T	p.Leu61Phe	missense_variant	Exon 4 of 4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.289G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1 link	n.225C>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;AS_VQSR

AF:

0.00

AC:

AN:

1083851

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352161

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Aug 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 61 of the NDP protein (p.Leu61Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NDP-related conditions and/or Norrie disease (PMID: 1307245, 9143918, 36729443). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 10690). 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. This variant disrupts the p.Leu61 amino acid residue in NDP. Other variant(s) that disrupt this residue have been observed in individuals with NDP-related conditions (PMID: 7627181, 9143918, 17296899), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2013

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

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

.;.;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.90

L;L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

.;N;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.014

.;D;.

Sift4G

Benign

0.063

.;T;.

Polyphen

1.0

D;D;D

Vest4

0.90

MutPred

0.79

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.98

MPC

0.98

ClinPred

0.88

GERP RS

6.0

Varity_R

0.87

gMVP

0.91

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

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