Menu
GeneBe

X-43949813-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_000266.4(NDP):c.388G>T(p.Glu130Ter) variant causes a stop gained 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 (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

NDP
NM_000266.4 stop_gained

Scores

2
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.67
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-AS1 (HGNC:40395): (NDP antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0348 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-43949813-C-A is Pathogenic according to our data. Variant chrX-43949813-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2430453.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NDPNM_000266.4 linkuse as main transcriptc.388G>T p.Glu130Ter stop_gained 3/3 ENST00000642620.1
NDP-AS1NR_046631.1 linkuse as main transcriptn.82C>A non_coding_transcript_exon_variant 1/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NDPENST00000642620.1 linkuse as main transcriptc.388G>T p.Glu130Ter stop_gained 3/3 NM_000266.4 P1
NDP-AS1ENST00000435093.1 linkuse as main transcriptn.82C>A non_coding_transcript_exon_variant 1/53
NDPENST00000647044.1 linkuse as main transcriptc.388G>T p.Glu130Ter stop_gained 4/4 P1
NDPENST00000470584.1 linkuse as main transcriptn.432G>T non_coding_transcript_exon_variant 3/32

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1063522
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
346926
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
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
23

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 submitterclinical testingGeneDxAug 19, 2022Observed in hemizygous state in two unrelated patients with features of NDP-related retinal vascular disorder in the published literature (Khetan et al., 2016; Tao et al., 2021) and not observed in hemizygous state in controls; Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 4 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34860240, 27380984) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
36
Dann
Uncertain
1.0
FATHMM_MKL
Uncertain
0.95
D
MutationTaster
Benign
1.0
D
Vest4
0.81
GERP RS
5.0

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.

Other links and lift over

hg19: chrX-43809059; API