rs377582530
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_001101426.4(CRPPA):c.933+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,462,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
CRPPA
NM_001101426.4 splice_donor_region, intron
NM_001101426.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.008477
2
Clinical Significance
Conservation
PhyloP100: 0.856
Genes affected
CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 7-16278126-T-C is Benign according to our data. Variant chr7-16278126-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387587.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRPPA | NM_001101426.4 | c.933+3A>G | splice_donor_region_variant, intron_variant | ENST00000407010.7 | |||
CRPPA | NM_001101417.4 | c.783+3A>G | splice_donor_region_variant, intron_variant | ||||
CRPPA | NM_001368197.1 | c.828+3A>G | splice_donor_region_variant, intron_variant | ||||
CRPPA | NR_160656.1 | n.998+3A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRPPA | ENST00000407010.7 | c.933+3A>G | splice_donor_region_variant, intron_variant | 5 | NM_001101426.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000798 AC: 17AN: 212954Hom.: 0 AF XY: 0.0000784 AC XY: 9AN XY: 114778
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GnomAD4 exome AF: 0.0000221 AC: 29AN: 1309830Hom.: 0 Cov.: 19 AF XY: 0.0000213 AC XY: 14AN XY: 656220
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 12, 2016 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2023 | This sequence change falls in intron 6 of the ISPD gene. It does not directly change the encoded amino acid sequence of the ISPD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs377582530, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 387587). 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 is not likely to affect RNA splicing. 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. - |
Computational scores
Source:
Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at