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GeneBe

rs1555976049

chrX-43949889-C-CTTCA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000266.4(NDP):c.311_312insTGAA(p.Lys104AsnfsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Consequence

NDP
NM_000266.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.64
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)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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. There are 33 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-43949889-C-CTTCA is Pathogenic according to our data. Variant chrX-43949889-C-CTTCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523342.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.311_312insTGAA p.Lys104AsnfsTer46 frameshift_variant 3/3 ENST00000642620.1
NDP-AS1NR_046631.1 linkuse as main transcriptn.159_162dup 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.311_312insTGAA p.Lys104AsnfsTer46 frameshift_variant 3/3 NM_000266.4 P1
NDP-AS1ENST00000435093.1 linkuse as main transcriptn.159_162dup non_coding_transcript_exon_variant 1/53
NDPENST00000647044.1 linkuse as main transcriptc.311_312insTGAA p.Lys104AsnfsTer46 frameshift_variant 4/4 P1
NDPENST00000470584.1 linkuse as main transcriptn.355_356insTGAA non_coding_transcript_exon_variant 3/32

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
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

Retinal detachment Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs1555976049; hg19: chrX-43809135; API