rs181195449
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting
The NM_001395891.1(CLASP1):​c.196-604C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 700,228 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: đť‘“ 0.00018 ( 0 hom., cov: 33)
Exomes đť‘“: 0.00016 ( 0 hom. )
Consequence
CLASP1
NM_001395891.1 intron
NM_001395891.1 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
CLASP1 (HGNC:17088): (cytoplasmic linker associated protein 1) CLASPs, such as CLASP1, are nonmotor microtubule-associated proteins that interact with CLIPs (e.g., CLIP170; MIM 179838). CLASP1 is involved in the regulation of microtubule dynamics at the kinetochore and throughout the spindle (Maiato et al., 2003 [PubMed 12837247]).[supplied by OMIM, Mar 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP5
Variant 2-121530929-G-A is Pathogenic according to our data. Variant chr2-121530929-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30184.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr2-121530929-G-A is described in Lovd as [Pathogenic]. Variant chr2-121530929-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.27). . Strength limited to SUPPORTING due to the PP5.
BS2
High AC in GnomAd4 at 27 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLASP1 | NM_001395891.1 | c.196-604C>T | intron_variant | ENST00000696935.1 | NP_001382820.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLASP1 | ENST00000696935.1 | c.196-604C>T | intron_variant | NM_001395891.1 | ENSP00000512981.1 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000123 AC: 16AN: 130504Hom.: 0 AF XY: 0.0000983 AC XY: 7AN XY: 71228
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GnomAD4 exome AF: 0.000164 AC: 90AN: 548048Hom.: 0 Cov.: 0 AF XY: 0.000135 AC XY: 40AN XY: 296756
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GnomAD4 genome AF: 0.000177 AC: 27AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74350
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2022 | This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs181195449, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive RNU4ATAC-related conditions (PMID: 21474761, 33059947). This variant is also known as g.50G>A. ClinVar contains an entry for this variant (Variation ID: 30184). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located within the 5' stem-loop region of the RNU4ATAC RNA, which includes the 15.5K binding site and is important for spliceosome assembly (PMID: 32628740). A significant number of disease-associated RNU4ATAC variants are found in this region (PMID: 32628740, 30368667). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 25, 2021 | The non-coding variant, n.50G>A, has been described in gnomAD with an allele frequency of 0.021% in the Non-Finnish European sub-population (dbSNP rsrs181195449). This sequence change is located in the 5' stem loop critical region, a region important for splicing (PMID:32628740). The n.50G>A has previously been observed in the compound heterozygous state with the n.51G>A pathogenic sequence change in an individual with intrauterine growth retardation, microcephaly, agenesis of the corpus callosum, and polymicrogyria (PMID: 21474761). Based on this information this variant is being classified as likely pathogenic. - |
Roifman syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephalic osteodysplastic primordial dwarfism, type I (MOPD1) (MIM# 210710) and Roifman syndrome (MIM# 616651). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0218 - Non-coding variant without predicted effect on gene expression of downstream targets. This small nuclear RNA forms part of a spliceosome essential for minor intron splicing (PMID: 26522830). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 27 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position is present in gnomAD (v2: 3 heterozygotes, 0 homozygotes). (I) 0601 - Variant is located in the well-established functional 5' stem-loop structure (PMID: 26522830). (SP) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. n.50G>C was identified in a MOPD1 patient who was compound heterozygous with n.51G>A (PMID: 21474761). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It was identified in a MOPD1 patient who was compound heterozygous with n.51G>A (PMID: 21474761). (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) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Jan 05, 2024 | - - |
Osteodysplastic primordial dwarfism, type 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 08, 2011 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at