rs754242194
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000642.3(AGL):c.2681+4dupA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000642.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.2681+4dupA | splice_region_variant, intron_variant | Intron 20 of 33 | ENST00000361915.8 | NP_000633.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250976Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135632
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461560Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727068
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glycogen storage disease type III Uncertain:3
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This sequence change falls in intron 20 of the AGL gene. It does not directly change the encoded amino acid sequence of the AGL protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs754242194, ExAC 0.002%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 17047887). This variant is also known as IVS21+5insA. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease III (GSD III; MIM#232400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252- This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable non-canonical variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as a VUS in ClinVar, in two unaffected carriers (Invitae - via personal communication). In addition, it has been reported in a Turkish homozygote individual with GSD III (PMID: 17047887). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at