rs727504031
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000266.4(NDP):c.220C>T(p.Arg74Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000266.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDP | NM_000266.4 | c.220C>T | p.Arg74Cys | missense_variant | 3/3 | ENST00000642620.1 | |
NDP-AS1 | NR_046631.1 | n.250G>A | non_coding_transcript_exon_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDP | ENST00000642620.1 | c.220C>T | p.Arg74Cys | missense_variant | 3/3 | NM_000266.4 | P1 | ||
NDP-AS1 | ENST00000435093.1 | n.250G>A | non_coding_transcript_exon_variant | 1/5 | 3 | ||||
NDP | ENST00000647044.1 | c.220C>T | p.Arg74Cys | missense_variant | 4/4 | P1 | |||
NDP | ENST00000470584.1 | n.264C>T | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | ClinVar contains an entry for this variant (Variation ID: 167326). This missense change has been observed in individuals with Norrie disease and congenital blindness (PMID: 1307245, 15776010, 22563645, 23141577). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the NDP protein (p.Arg74Cys). - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 15, 2014 | - - |
Atrophia bulborum hereditaria Pathogenic:1
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Nov 12, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at