20-50935214-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_003859.3(DPM1):c.701G>A(p.Arg234His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,606,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_003859.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DPM1 | NM_003859.3 | c.701G>A | p.Arg234His | missense_variant | Exon 9 of 9 | ENST00000371588.10 | NP_003850.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000666 AC: 1AN: 150098Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250468Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135400
GnomAD4 exome AF: 0.00000755 AC: 11AN: 1456528Hom.: 0 Cov.: 28 AF XY: 0.00000828 AC XY: 6AN XY: 724922
GnomAD4 genome AF: 0.00000666 AC: 1AN: 150098Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 73198
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.701G>A (p.R234H) alteration is located in exon 9 (coding exon 9) of the DPM1 gene. This alteration results from a G to A substitution at nucleotide position 701, causing the arginine (R) at amino acid position 234 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
The R234H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R234H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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. -
Congenital disorder of glycosylation type 1E Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 234 of the DPM1 protein (p.Arg234His). This variant is present in population databases (rs760322056, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429484). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at