chr2-121530892-C-T

Position:

chr2-121530892-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13U:1

Conservation

PhyloP100: 5.71

Variant links:

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]

CLASP1 links:

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]

RNU4ATAC links:

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

CLASP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
CLASP1	NM_001395891.1 link	c.196-567G>A		intron_variant		ENST00000696935.1	NP_001382820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1 link	c.196-567G>A		intron_variant			NM_001395891.1	ENSP00000512981.1		A0A8V8TLP7

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

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:

AN:

129764

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

70856

show subpopulations

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.:

Cov.:

AF XY:

0.000568

AC XY:

166

AN XY:

292136

show subpopulations

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:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.000393

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Roifman syndrome

Pathogenic:6Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Oct 02, 2019	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Uncertain significance, flagged submission	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 22, 2022	ACMG classification criteria: PS3 supporting, PM3 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 12, 2024	Criteria applied: PM3_VSTR,PM2,PS3_SUP,PP1 -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	RNU4ATAC: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Apr 19, 2023	PS4_MOD, PP1, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 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 (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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 18, 2019	- -

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 23, 2022

- -

CLASP1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2024

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over