NM_001478.5:c.263dupG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001478.5(B4GALNT1):c.263dupG(p.Leu89ProfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,610,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001478.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000528 AC: 8AN: 151652Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.000132 AC: 193AN: 1459040Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104AN XY: 725892
GnomAD4 genome AF: 0.0000528 AC: 8AN: 151652Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6AN XY: 74054
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 26 Pathogenic:7
PVS1+PM3+PM2_Supporting -
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The p.Leu89ProfsX13 variant in B4GALNT1 has been reported in the homozygous state, in at least 3 individuals with hereditary spastic paraplegia (Boukhris 2013 PMID: 23746551, Rose 2020 PMID: 31812852, Hengel 2020 PMID: 32214227). At least two of these individuals were from consanguineous parents. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 60525) and has been identified in 0.01% (5/67846) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This is consistent with the prevalence of the disease in the general population. In vitro functional studies provide some evidence that this variant impacts protein function as in vitro cell-free enzyme assays showed no residual enzyme activity for this variant (Bhuiyan 2019 PMID: 30521973). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 89 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the B4GALNT1 gene is an established disease mechanism in autosomal recessive hereditary spastic paraplegia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hereditary spastic paraplegia. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting, PS3_Supporting. -
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not provided Pathogenic:2
The c.263dupG variant in the B4GALNT1 gene has been reported previously in the homozygous state in an individual with hereditary spastic paraplegia with learning disability, lower limb spasticity and weakness, nystagmus, axonal sensitive neuropathy, white matter hyperintensities, and cerebral atrophy (Boukhris et al., 2013). The c.263dupG variant causes a frameshift starting with codon Leucine 89, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Leu89ProfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.263dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.263dupG as a likely pathogenic variant. -
PM2, PM3, PS3, PVS1 -
Spastic paraplegia Pathogenic:1
This sequence change creates a premature translational stop signal (p.Leu89Profs*13) in the B4GALNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in B4GALNT1 are known to be pathogenic (PMID: 23746551). 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. This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23746551, 32214227). ClinVar contains an entry for this variant (Variation ID: 60525). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at