1-45327257-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_032756.4(HPDL):c.109C>T(p.Arg37Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,906 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_032756.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000873 AC: 2AN: 229206Hom.: 0 AF XY: 0.0000159 AC XY: 2AN XY: 126132
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1450906Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2AN XY: 721450
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.109C>T (p.R37W) alteration is located in exon 1 (coding exon 1) of the HPDL gene. This alteration results from a C to T substitution at nucleotide position 109, causing the arginine (R) at amino acid position 37 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/229206) total alleles studied. The highest observed frequency was 0.003% (1/33410) of Latino alleles. Another alteration at the same codon, c.110G>C (p.R37P), has been reported in an individual with features consistent with HPDL-related neurological disorder (Wiessner, 2021). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at