chrX-43949932-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000266.4(NDP):c.269G>C(p.Arg90Pro) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 23)
Consequence
NDP
NM_000266.4 missense
NM_000266.4 missense
Scores
5
5
2
Clinical Significance
Conservation
PhyloP100: 3.70
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chrX-43949933-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373948.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.904
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDP | NM_000266.4 | c.269G>C | p.Arg90Pro | missense_variant | 3/3 | ENST00000642620.1 | |
NDP-AS1 | NR_046631.1 | n.201C>G | non_coding_transcript_exon_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDP | ENST00000642620.1 | c.269G>C | p.Arg90Pro | missense_variant | 3/3 | NM_000266.4 | P1 | ||
NDP-AS1 | ENST00000435093.1 | n.201C>G | non_coding_transcript_exon_variant | 1/5 | 3 | ||||
NDP | ENST00000647044.1 | c.269G>C | p.Arg90Pro | missense_variant | 4/4 | P1 | |||
NDP | ENST00000470584.1 | n.313G>C | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Atrophia bulborum hereditaria Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1992 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1307245, 22786811, 8298646, 23871722) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;D
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;N
MutationTaster
Benign
A
PrimateAI
Uncertain
T
Polyphen
D;D;D
Vest4
0.89
MutPred
Loss of MoRF binding (P = 0.0058);Loss of MoRF binding (P = 0.0058);Loss of MoRF binding (P = 0.0058);
MVP
1.0
MPC
1.7
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