12-57626790-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001478.5(B4GALNT1):āc.1556G>Cā(p.Arg519Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001478.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251486Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Published functional studies demonstrate that the R519P variant leads to a loss of function with no GM2 biosynthesis detected (PMID: 35775650); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35775650) -
Spastic paraplegia Uncertain:1
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 519 of the B4GALNT1 protein (p.Arg519Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with B4GALNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 848217). 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: "Tolerated"; 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