rs750325275
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PP5_Very_StrongBP4BS2
The NM_001395891.1(CLASP1):c.196-570C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 693,922 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 (โ โ ).
Frequency
Genomes: ๐ 0.00014 ( 0 hom., cov: 32)
Exomes ๐: 0.000090 ( 0 hom. )
Consequence
CLASP1
NM_001395891.1 intron
NM_001395891.1 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 9.16
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 Uncertain_significance. Variant got 3 ACMG points.
PP5
?
Variant 2-121530895-G-A is Pathogenic according to our data. Variant chr2-121530895-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-121530895-G-A is described in Lovd as [Pathogenic]. Variant chr2-121530895-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.21).. Strength limited to SUPPORTING due to the PP5.
BS2
?
High AC in GnomAd at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLASP1 | NM_001395891.1 | c.196-570C>T | intron_variant | ENST00000696935.1 | |||
RNU4ATAC | NR_023343.1 | n.16G>A | non_coding_transcript_exon_variant | 1/1 | |||
CLASP1-AS1 | XR_001739683.2 | n.608+120G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLASP1 | ENST00000696935.1 | c.196-570C>T | intron_variant | NM_001395891.1 | A2 | ||||
RNU4ATAC | ENST00000580972.1 | n.15G>A | non_coding_transcript_exon_variant | 1/1 | |||||
CLASP1-AS1 | ENST00000577914.1 | n.354+120G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152102Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000146 AC: 19AN: 129796Hom.: 0 AF XY: 0.000141 AC XY: 10AN XY: 70866
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GnomAD4 exome AF: 0.0000904 AC: 49AN: 541820Hom.: 0 Cov.: 0 AF XY: 0.0000889 AC XY: 26AN XY: 292346
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Roifman syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | Dec 08, 2022 | - - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital | Feb 28, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jan 27, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 02, 2015 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | RNU4ATAC: PM3:Very Strong, PM2, PP1:Moderate - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 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 (rs750325275, gnomAD 0.04%). This variant has been observed in individuals with Roifman syndrome (PMID: 26522830, 28669401, 29263834, 29391254, 32595695). It has also been observed to segregate with disease in related individuals. This variant is also known as c.196-570C>T and 122288471 G>A. ClinVar contains an entry for this variant (Variation ID: 218082). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 06, 2023 | - - |
Short stature;C3714756:Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | May 24, 2019 | The NR_023343.1:n.16G>A a non coding transcript variant has been observed in the homozygous state or as a compound heterozygous, in trans with another disease-causing variant in association with autosomal recessive Roifman syndrome [MIM#616651] or autosomal recessivemicrocephalic osteodysplastic primordial dwarfism type 1 (MOPD1) [MIM#210710] [PMID: 29391254; PMID: 29263834; PMID:26522830]. The variant has 0.014% allele frequency in the gnomAD database (23 out of 161,196 heterozygous alleles) indicating this is a rare variant. Based on the available evidence, the variant n.16G>A is classified as Pathogenic - |
Lowry-Wood syndrome;C1846059:Roifman syndrome;C1859452:Osteodysplastic primordial dwarfism, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 19, 2022 | - - |
Computational scores
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Name
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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