rs386833426
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000027.4(AGA):c.395-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000079 in 1,518,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000027.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGA | NM_000027.4 | c.395-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000264595.7 | |||
AGA | NM_001171988.2 | c.395-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
AGA | XM_047449722.1 | c.395-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
AGA | NR_033655.2 | n.457-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGA | ENST00000264595.7 | c.395-8A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000027.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151966Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250390Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135470
GnomAD4 exome AF: 0.00000805 AC: 11AN: 1366186Hom.: 0 Cov.: 24 AF XY: 0.00000730 AC XY: 5AN XY: 685304
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151966Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74216
ClinVar
Submissions by phenotype
Aspartylglucosaminuria Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 20, 2023 | Variant summary: AGA c.395-8A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site, and three of four predict the variant also abolishes/weakens the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing by creating an alternative 3' acceptor site upstream from the canonical 3' acceptor site, resulting in a 7 bp insertion which ultimately leads to a frameshift and premature termination codon. The variant allele was found at a frequency of 8e-06 in 250390 control chromosomes (gnomAD). c.395-8A>G has been reported in the literature in the homozygous state in two siblings affected with Aspartylglucosaminuria (Yoshida_1992). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in an unstable protein with <10% of normal activity when expressed in vitro (Saarela_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11309371, 1427775). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 27, 2023 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at