chr2-121530887-C-T

Variant names:

• chr2-121530887-C-T
• rs370715569
• NM_001395891.1:c.196-562G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5 BP4 BS2_Supporting

The NM_001395891.1(CLASP1):​c.196-562G>A variant causes a intron change. The variant allele was found at a frequency of 0.000426 in 692,974 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 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 5.74

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]

CLASP1-AS1 (HGNC:55328): (CLASP1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP5: Variant 2-121530887-C-T is Pathogenic according to our data. Variant chr2-121530887-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218086.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, Pathogenic=1}. Variant chr2-121530887-C-T is described in Lovd as [Pathogenic]. Variant chr2-121530887-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 60 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 rank	MANE	Protein	UniProt
CLASP1	NM_001395891.1	c.196-562G>A		intron_variant	Intron 2 of 40	ENST00000696935.1	NP_001382820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-562G>A		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000386 AC: 50 AN: 129556 Hom.: 0 AF XY: 0.000410 AC XY: 29 AN XY: 70760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000385

Gnomad SAS exome AF: 0.000539

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000486

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000435 AC: 235 AN: 540682 Hom.: 0 Cov.: 0 AF XY: 0.000453 AC XY: 132 AN XY: 291570

Gnomad4 AFR exome AF: 0.000128

Gnomad4 AMR exome AF: 0.000465

Gnomad4 ASJ exome AF: 0.0000502

Gnomad4 EAS exome AF: 0.000314

Gnomad4 SAS exome AF: 0.000529

Gnomad4 FIN exome AF: 0.0000906

Gnomad4 NFE exome AF: 0.000527

Gnomad4 OTH exome AF: 0.000167

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74468

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000408

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Roifman syndrome Pathogenic:2

Nov 02, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_STR,PM2 -

not provided Pathogenic:2

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (rs370715569, gnomAD 0.05%). This variant has been observed in individual(s) with clinical features of RNU4ATAC-related conditions (PMID: 26522830; internal data). 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: 218086). Algorithms developed to predict the effect of variants on gene product 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. -

Nov 30, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RNU4ATAC-related disorder Pathogenic:1

Jan 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RNU4ATAC n.8C>T is a noncoding alteration. This variant has been reported in the compound heterozygous state in an individual with Roifman syndrome (Subject 6, Kindred K4, Merico et al. 2015. PubMed ID: 26522830). This variant is located in an element of major importance for splicing and is classified as a Roifman syndrome causal variant (Figure 3, Merico et al. 2015. PubMed ID: 26522830). A different substitution affecting the same nucleotide (n.8C>A) has been reported in the compound heterozygous state in an individual with Lowry-Wood syndrome (Shelihan et al. 2018. PubMed ID: 30368667). This variant is reported in 0.054% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288463-C-T). This variant is interpreted as likely pathogenic. -

Spondyloepiphyseal dysplasia congenita Pathogenic:1

Mar 04, 2020

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jun 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RNU4ATAC n.8C>T alters a nucleotide in the non-coding RNA and located in Stem II region (n.3-n.19, element of major importance for splicing; Merico_2015) of RNU4ATAC. Additionally, Stem II, which base pair the U6atac, required to form the catalytically active minor spliceosome (PMID: 29263834). The variant allele was found at a frequency of 0.00039 in 129556 control chromosomes (gnomAD). n.8C>T has been reported in the literature in at least one compound heterozygous individual affected with Roifman Syndrome (Merico_2015) and one individual with RNU4ATAC-related conditions reported in one ClinVar lab. These data indicate that the variant may be associated with disease. At least one functional study reports this variant results in reducing splicing efficiency in transfected cells (Benoit-Pilven_2020). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Craniosynostosis syndrome;C0349588:Short stature;C0878544:Cardiomyopathy;C4022738:Neurodevelopmental delay;C4551563:Microcephaly Uncertain:1

Apr 20, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370715569; hg19: chr2-122288463;