rs786200938
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_080605.4(B3GALT6):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 834,202 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 Pathogenic (★).
Frequency
Consequence
NM_080605.4 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000479 AC: 4AN: 834202Hom.: 0 Cov.: 29 AF XY: 0.00000259 AC XY: 1AN XY: 385392
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Al-Gazali syndrome;C3809210:Ehlers-Danlos syndrome, spondylodysplastic type, 2;C4017377:Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures Pathogenic:1
This sequence change affects methionine residue at the initiation codon of the B3GALT6 mRNA (p.Met1?). Different varaints disrupting the initiator codon of B3GALT6 gene have been reported in multiple unrelated patients with Spondyloepimetaphyseal dysplasia with joint laxity (PMID: 23664117, ClinVar ID: 1067539, 1452181, 2151860). The same location with a different neucleotide change affecting the initiation codon, c.1A>G (p.Met1?), has been reported in four Japanese families with Spondyloepimetaphyseal dysplasia with joint laxity (PMID: 23664117). Functional study demonstrated the mutant B3GALT6 protein with c.1A>G had a molecular weight ~4 kD lower compared with the wildtype protein, suggesting the mutation in the initiation codon probably resulted in an N-terminal deletion of 41 amino acids (PMID: 23664117). The c.1A>C variant is currently not reported in any pateints nor in the gnomAD database (v2.1.1). Therefore, it is interpreted as pathogenic according to ACMG/AMP guidelines. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at