chrX-43949932-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5
The NM_000266.4(NDP):c.269G>A(p.Arg90His) variant causes a missense change. The variant allele was found at a frequency of 0.0000655 in 1,205,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000266.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NDP | NM_000266.4 | c.269G>A | p.Arg90His | missense_variant | 3/3 | ENST00000642620.1 | |
NDP-AS1 | NR_046631.1 | n.201C>T | non_coding_transcript_exon_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NDP | ENST00000642620.1 | c.269G>A | p.Arg90His | missense_variant | 3/3 | NM_000266.4 | P1 | ||
NDP-AS1 | ENST00000435093.1 | n.201C>T | non_coding_transcript_exon_variant | 1/5 | 3 | ||||
NDP | ENST00000647044.1 | c.269G>A | p.Arg90His | missense_variant | 4/4 | P1 | |||
NDP | ENST00000470584.1 | n.313G>A | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000269 AC: 3AN: 111565Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1AN XY: 33755
GnomAD3 exomes AF: 0.0000236 AC: 4AN: 169831Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 56509
GnomAD4 exome AF: 0.0000695 AC: 76AN: 1093622Hom.: 0 Cov.: 30 AF XY: 0.0000528 AC XY: 19AN XY: 359720
GnomAD4 genome ? AF: 0.0000269 AC: 3AN: 111565Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1AN XY: 33755
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 90 of the NDP protein (p.Arg90His). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg90 amino acid residue in NDP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14635119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDP protein function. ClinVar contains an entry for this variant (Variation ID: 812352). This missense change has been observed in individual(s) with Norrie disease (PMID: 31456290). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2019 | See Variant Classification Assertion Criteria. - |
Benign, criteria provided, single submitter | clinical testing | Laboratoire Génétique Moléculaire, CHRU TOURS | Jun 04, 2019 | - - |
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PM2_Moderate, PM5_Moderate, PP3_Supporting - |
Atrophia bulborum hereditaria Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2024 | Variant summary: NDP c.269G>A (p.Arg90His) results in a non-conservative amino acid change located in the Cystine knot, C-terminal (IPR006207) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 1205187 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NDP causing Atrophia bulborum hereditaria (6.6e-05 vs ND), allowing no conclusion about variant significance. c.269G>A has been reported in the literature in individuals affected with Atrophia bulborum hereditaria. These report(s) do not provide unequivocal conclusions about association of the variant with Atrophia bulborum hereditaria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 812352). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at