chr2-15238670-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_015909.4(NBAS):c.5741G>A(p.Arg1914His) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,592,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_015909.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000152 AC: 2AN: 131546Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000283 AC: 7AN: 247526Hom.: 0 AF XY: 0.0000298 AC XY: 4AN XY: 134044
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460796Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 726714
GnomAD4 genome AF: 0.0000152 AC: 2AN: 131546Hom.: 0 Cov.: 32 AF XY: 0.0000158 AC XY: 1AN XY: 63134
ClinVar
Submissions by phenotype
not provided Pathogenic:3
The R1914H pathogenic variant in the NBAS gene has been reported previously either in the homozygous state or in combination with another NBAS variant in multiple individuals with features of NBAS-related disorder, but liver disease was not reported in all individuals (Maksimova et al., 2010; Trakadis et al., 2014; Kim et al., 2017; Kortum et al., 2017; Park et al., 2017; Balasubramanian et al., 2017). The R1914H variant is observed in 4/16,484 (0.02%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). Although the R1914H variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1914H as a pathogenic variant. -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1914 of the NBAS protein (p.Arg1914His). This variant is present in population databases (rs369698072, gnomAD 0.02%). This missense change has been observed in individual(s) with short stature, optic nerve atrophy, and Pelger-Huet (SOPH) anomaly (PMID: 20577004, 24884844, 27789416, 28031453, 28115293, 28425089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37042). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NBAS protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at