rs374299350
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS2_Supporting
The NM_001395891.1(CLASP1):c.196-584C>T variant causes a intron change. The variant allele was found at a frequency of 0.0000601 in 699,036 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )
Consequence
CLASP1
NM_001395891.1 intron
NM_001395891.1 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.66
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]
RNU4ATAC (HGNC:34016): (RNA, U4atac small nuclear) The small nuclear RNA (snRNA) encoded by this gene is part of the U12-dependent minor spliceosome complex. In addition to the encoded RNA, this ribonucleoprotein complex consists of U11, U12, U5, and U6atac snRNAs. The U12-dependent spliceosome acts on approximately 700 specific introns in the human genome. Defects in this gene are a cause of microcephalic osteodysplastic primordial dwarfism type 1 (MOPD). [provided by RefSeq, Jul 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PP5
?
Variant 2-121530909-G-A is Pathogenic according to our data. Variant chr2-121530909-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-121530909-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.3). . Strength limited to SUPPORTING due to the PP5.
BS2
?
High AC in GnomAd4 at 8 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 | UniProt |
---|---|---|---|---|---|---|---|
CLASP1 | NM_001395891.1 | c.196-584C>T | intron_variant | ENST00000696935.1 | |||
RNU4ATAC | NR_023343.1 | n.30G>A | non_coding_transcript_exon_variant | 1/1 | |||
CLASP1-AS1 | XR_001739683.2 | n.608+134G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLASP1 | ENST00000696935.1 | c.196-584C>T | intron_variant | NM_001395891.1 | A2 | ||||
RNU4ATAC | ENST00000580972.1 | n.29G>A | non_coding_transcript_exon_variant | 1/1 | |||||
CLASP1-AS1 | ENST00000577914.1 | n.354+134G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000613 AC: 8AN: 130408Hom.: 0 AF XY: 0.0000562 AC XY: 4AN XY: 71180
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GnomAD4 exome AF: 0.0000622 AC: 34AN: 546738Hom.: 0 Cov.: 0 AF XY: 0.0000575 AC XY: 17AN XY: 295832
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteodysplastic primordial dwarfism, type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Jan 01, 2018 | The same individual also harbours another variant g.122288495C>T in the same gene along with this variant as compound heterozygote - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 08, 2011 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | 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 (rs374299350, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of microcephalic osteodysplastic primordial dwarfism type 1 (PMID: 21474760). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30180). Functional studies have shown that this variant disrupts ncRNA function (PMID: 21474760). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
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