rs756026847

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001395891.1(CLASP1):c.196-591C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000901 in 699,402 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 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

CLASP1
NM_001395891.1 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:2

Conservation

PhyloP100: 9.43

Publications

2 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP5

Variant 2-121530916-G-A is Pathogenic according to our data. Variant chr2-121530916-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218084.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=3}.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 13 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 link	c.196-591C>T		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 link	c.196-591C>T		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1		A0A8V8TLP7

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000613

AC:

AN:

130446

AF XY:

0.0000702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000914

AC:

AN:

547192

Hom.:

Cov.:

AF XY:

0.0000945

AC XY:

AN XY:

296150

show subpopulations

African (AFR)

AF:

0.0000636

AC:

AN:

15720

American (AMR)

AF:

0.00

AC:

AN:

34696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20006

East Asian (EAS)

AF:

0.0000312

AC:

AN:

32068

South Asian (SAS)

AF:

0.0000319

AC:

AN:

62648

European-Finnish (FIN)

AF:

0.0000904

AC:

AN:

33190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2440

European-Non Finnish (NFE)

AF:

0.000136

AC:

AN:

316048

Other (OTH)

AF:

0.00

AC:

AN:

30376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Roifman syndrome

Pathogenic:2Uncertain:1

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 signficiantly reduced splicing efficiencies (PMID: 32628740). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the nucleotide is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0600 - Variant is located in the functionally important 5' Stem-Loop region of the small nuclear RNA (PMID: 32628740). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic (ClinVar), and observed in compound heterozygous siblings with Roifman syndrome (PMID: 26522830 PMID: 32628740). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (n.13C>T) in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 02, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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 supporting -

RNU4ATAC-related disorder

Pathogenic:1

Jan 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RNU4ATAC n.37G>A is a noncoding alteration. This variant has been reported in the compound heterozygous state in an individual with Roifman syndrome (Subject 1-2, Kindred K1, 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 casual variant (Figure 3, Merico et al. 2015. PubMed ID: 26522830). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288492-G-A) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/218084/). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Dec 18, 2024

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 (rs756026847, gnomAD 0.01%). This variant has been observed in individual(s) with RNU4ATAC-related conditions (PMID: 32628740; internal data). 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: 218084). Functional studies have shown that this variant disrupts ncRNA splicing (PMID: 32628740). 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). For these reasons, this variant has been classified as Pathogenic. -

Spondyloepiphyseal dysplasia congenita

Pathogenic:1

Mar 04, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteodysplastic primordial dwarfism, type 1

Pathogenic:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Pathogenic:1

Feb 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CLASP1-related disorder

Uncertain:1

Jul 30, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

9.4

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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rs756026847

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over