rs1302861734

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000266.4(NDP):c.346C>T(p.Leu116Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000185 in 1,078,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86

Publications

0 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: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000266.4

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.346C>T	p.Leu116Phe	missense_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.124G>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.346C>T	p.Leu116Phe	missense_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.346C>T	p.Leu116Phe	missense_variant	Exon 4 of 4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.124G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1 link	n.390C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000690

AC:

AN:

144865

AF XY:

0.0000225

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000185

AC:

AN:

1078178

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

351546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25997

American (AMR)

AF:

0.00

AC:

AN:

32092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18957

East Asian (EAS)

AF:

0.00

AC:

AN:

29065

South Asian (SAS)

AF:

0.00

AC:

AN:

51329

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.00000240

AC:

AN:

832131

Other (OTH)

AF:

0.00

AC:

AN:

45370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 116 of the NDP protein (p.Leu116Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NDP-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.55

N;N;N

PhyloP100

4.9

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.2

.;N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.017

.;D;.

Sift4G

Benign

0.072

.;T;.

Polyphen

0.92

P;P;P

Vest4

0.31

MutPred

0.25

Loss of catalytic residue at M114 (P = 0.0154);Loss of catalytic residue at M114 (P = 0.0154);Loss of catalytic residue at M114 (P = 0.0154);

MVP

0.83

MPC

1.1

ClinPred

0.56

GERP RS

6.0

Varity_R

0.68

gMVP

0.94

Mutation Taster

=71/29

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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