2-121530892-C-T

Variant names:

• chr2-121530892-C-T
• rs559979281
• NM_001395891.1:c.196-567G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001395891.1(CLASP1):​c.196-567G>A variant causes a intron change. The variant allele was found at a frequency of 0.000497 in 693,814 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 5.71

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_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 2-121530892-C-T is Pathogenic according to our data. Variant chr2-121530892-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 218083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-121530892-C-T is described in Lovd as [Pathogenic]. Variant chr2-121530892-C-T is described in Lovd as [Pathogenic]. Variant chr2-121530892-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLASP1	NM_001395891.1	c.196-567G>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.196-567G>A		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000347 AC: 45 AN: 129764 Hom.: 0 AF XY: 0.000353 AC XY: 25 AN XY: 70856

Gnomad AFR exome AF: 0.000329

Gnomad AMR exome AF: 0.000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000962

Gnomad SAS exome AF: 0.000449

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000465

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000534 AC: 289 AN: 541512 Hom.: 0 Cov.: 0 AF XY: 0.000568 AC XY: 166 AN XY: 292136

Gnomad4 AFR exome AF: 0.000385

Gnomad4 AMR exome AF: 0.000320

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000251

Gnomad4 SAS exome AF: 0.000496

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000674

Gnomad4 OTH exome AF: 0.000565

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74470

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000359 Hom.: 0

Bravo AF: 0.000393

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Roifman syndrome Pathogenic:6 Uncertain:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 22, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM3 moderated -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 (MIM#210710), Roifman syndrome (MIM#616651), and Lowry-Wood syndrome (MIM#226960). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. Transfected cells were proven to demonstrate significantly reduced splicing efficiencies (PMID: 32628740). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position, is present in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the functionally important stem II region of the small nuclear RNA (PMID: 32628740). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous individuals with Roifman syndrome (ClinVar, PMID: 32628740). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 08, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RNU4ATAC n.13C>T alters a conserved nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00035 in 129764 control chromosomes. n.13C>T has been reported in the literature in multiple individuals affected with Roifman Syndrome (example Merico_2015, Maddirevula_ 2018, Bhattad_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37898571, 29620724, 26522830). ClinVar contains an entry for this variant (Variation ID: 218083). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 12, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PM2,PS3_SUP,PP1 -

Oct 02, 2019

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:5

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNU4ATAC: PM3:Very Strong, PP1:Moderate, PM2:Supporting, PS3:Supporting -

Apr 19, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_MOD, PP1, PS3, PM3 -

Feb 18, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 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 (rs559979281, gnomAD 0.06%). This variant has been observed in individual(s) with Roifman syndrome (PMID: 26522830, 28623346, 30455926, 32109076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218083). Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lowry-Wood syndrome;C1846059:Roifman syndrome;C1859452:Osteodysplastic primordial dwarfism, type 1 Pathogenic:1

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CLASP1-related disorder Pathogenic:1

Aug 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CLASP1 c.196-567G>A variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with other noncoding variants in RNU4ATAC in patients with Roifman syndrome (Merico et al. 2015. PubMed ID: 26522830; Bogaert et al. 2017. PubMed ID: 28623346; Hallermayr et al. 2018. PubMed ID: 30455926; Wang et al. 2020. PubMed ID: 32109076). Functional studies showed that this variant disrupts ncRNA function (Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.95

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: rs559979281; hg19: chr2-122288468;