rs745594160
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000485.3(APRT):c.400+2_400+3insT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,612,988 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000485.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APRT | NM_000485.3 | c.400+2_400+3insT | splice_region_variant, intron_variant | ENST00000378364.8 | |||
APRT | NM_001030018.2 | c.400+2_400+3insT | splice_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APRT | ENST00000378364.8 | c.400+2_400+3insT | splice_region_variant, intron_variant | 1 | NM_000485.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152226Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250836Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135750
GnomAD4 exome AF: 0.000199 AC: 291AN: 1460762Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 168AN XY: 726698
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152226Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change falls in intron 4 of the APRT gene. It does not directly change the encoded amino acid sequence of the APRT protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in APRT cause disease. This variant is present in population databases (rs745594160, gnomAD 0.02%). This variant has been observed in individual(s) with adenine phosphoribosyltransferase (APRT) deficiency (PMID: 3680503, 11243733, 30355577). This variant is also known as IVS4+2insT. ClinVar contains an entry for this variant (Variation ID: 203396). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 3680503). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | APRT: PM2, PP3 - |
Adenine phosphoribosyltransferase deficiency Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | APRT Deficiency Research Program of the Rare Kidney Stone Consortium, Landspitali, National University Hospital of Iceland | Sep 01, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at