1-193122332-G-A
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_024529.5(CDC73):c.131+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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_024529.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDC73 | NM_024529.5 | c.131+1G>A | splice_donor_variant | ENST00000367435.5 | |||
CDC73 | XM_006711537.5 | c.131+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDC73 | ENST00000367435.5 | c.131+1G>A | splice_donor_variant | 1 | NM_024529.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727184
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Parathyroid carcinoma Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 3276). This variant is also known as IVS1+1G>A. Disruption of this splice site has been observed in individual(s) with familial isolated primary hyperparathyroidism (PMID: 15531515, 16061557). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the CDC73 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDC73 are known to be pathogenic (PMID: 12434154). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Parathyroid adenoma, somatic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Parathyroid carcinoma;C1704981:Hyperparathyroidism 2 with jaw tumors;C1840402:Hyperparathyroidism 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 06, 2021 | - - |
Hyperparathyroidism 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2018 | The c.131+1G>A splice site variant in the CDC73 gene has been previously reported in association with multiple families with hyperparathyroidism and parathyroid tumors (Cetani et al., 2004; Bradley et al., 2005). Functional studies show c.131+1G>A results in loss of 30 nucleotides from exon 1 of the CDC73 gene (Bradley et al., 2005). Based on currently available evidence, we consider c.131+1G>A to be pathogenic, and its presence consistent with a diagnosis of a CDC73-related disorder - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 16, 2021 | The c.131+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the CDC73 gene. This variant has been detected in multiple individuals with primary hyperparathyroidism and reported to result in partial skipping of exon 1 (Cetani F et al. J Clin Endocrinol Metab, 2004 Nov;89:5583-91; Bradley KJ et al. J Med Genet, 2005 Aug;42:e51; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at