rs104894880
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000266.4(NDP):c.181C>T(p.Leu61Phe) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L61I) has been classified 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 missense
NM_000266.4 missense
Scores
8
5
4
Clinical Significance
Conservation
PhyloP100: 5.38
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 9 ACMG points.
PM1
In a disulfide_bond (size 55) in uniprot entity NDP_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938
PP5
Variant X-43950020-G-A is Pathogenic according to our data. Variant chrX-43950020-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10690.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-43950020-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NDP | NM_000266.4 | c.181C>T | p.Leu61Phe | missense_variant | 3/3 | ENST00000642620.1 | NP_000257.1 | |
NDP-AS1 | NR_046631.1 | n.289G>A | non_coding_transcript_exon_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NDP | ENST00000642620.1 | c.181C>T | p.Leu61Phe | missense_variant | 3/3 | NM_000266.4 | ENSP00000495972 | P1 | ||
NDP-AS1 | ENST00000435093.1 | n.289G>A | non_coding_transcript_exon_variant | 1/5 | 3 | |||||
NDP | ENST00000647044.1 | c.181C>T | p.Leu61Phe | missense_variant | 4/4 | ENSP00000495811 | P1 | |||
NDP | ENST00000470584.1 | n.225C>T | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1083851Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 352161
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
1083851
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
352161
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2013 | - - |
Atrophia bulborum hereditaria Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Benign
.;N;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.
Sift4G
Benign
.;T;.
Polyphen
D;D;D
Vest4
0.90
MutPred
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
0.98
MPC
0.98
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