rs28933685
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000266.4(NDP):c.1A>G(p.Met1?) variant causes a start lost 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 (★★).
Frequency
Genomes: not found (cov: 24)
Consequence
NDP
NM_000266.4 start_lost
NM_000266.4 start_lost
Scores
6
1
2
Clinical Significance
Conservation
PhyloP100: 5.42
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000266.4 (NDP) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1687207
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-43958645-T-C is Pathogenic according to our data. Variant chrX-43958645-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDP | NM_000266.4 | c.1A>G | p.Met1? | start_lost | 2/3 | ENST00000642620.1 | |
NDP-AS1 | NR_046631.1 | n.467-2140T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDP | ENST00000642620.1 | c.1A>G | p.Met1? | start_lost | 2/3 | NM_000266.4 | P1 | ||
NDP-AS1 | ENST00000435093.1 | n.467-2140T>C | intron_variant, non_coding_transcript_variant | 3 | |||||
NDP | ENST00000647044.1 | c.1A>G | p.Met1? | start_lost | 3/4 | P1 | |||
NDP | ENST00000470584.1 | n.218+73A>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atrophia bulborum hereditaria Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This sequence change affects the initiator methionine of the NDP mRNA. The next in-frame methionine is located at codon 12. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with Norrie disease (PMID: 7627181, 7814011, 14635119, 26547627). ClinVar contains an entry for this variant (Variation ID: 10687). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;T
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A
Polyphen
B;B;B
Vest4
0.82
MutPred
Loss of catalytic residue at M1 (P = 0.0199);Loss of catalytic residue at M1 (P = 0.0199);Loss of catalytic residue at M1 (P = 0.0199);
MVP
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at