rs750325275

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS2_Supporting

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 (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CLASP1
NM_001395891.1 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.16

Publications

3 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_pathogenic. The variant received 6 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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.21). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 22 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.196-570C>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.196-570C>T		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1		A0A8V8TLP7

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000146

AC:

AN:

129796

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000166

Gnomad ASJ exome

AF:

0.000248

Gnomad EAS exome

AF:

0.000480

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000904

AC:

AN:

541820

Hom.:

Cov.:

AF XY:

0.0000889

AC XY:

AN XY:

292346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15602

American (AMR)

AF:

0.000116

AC:

AN:

34434

Ashkenazi Jewish (ASJ)

AF:

0.0000502

AC:

AN:

19926

East Asian (EAS)

AF:

0.000125

AC:

AN:

31902

South Asian (SAS)

AF:

0.000112

AC:

AN:

62466

European-Finnish (FIN)

AF:

0.0000604

AC:

AN:

33136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2422

European-Non Finnish (NFE)

AF:

0.0000898

AC:

AN:

311830

Other (OTH)

AF:

0.0000997

AC:

AN:

30102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000145

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41414

American (AMR)

AF:

0.000131

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000144

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Roifman syndrome

Pathogenic:6

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance:Likely 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

- -

Feb 06, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Predicted consequence: non-coding transcript variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 29263834, 29391254). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 26522830, 29263834, 29391254). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000218082 / PMID: 26522830). Therefore, the variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 27, 2022

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 08, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:5

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 (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 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. -

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, PM2 -

Dec 06, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2019

Blueprint Genetics

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:2

May 24, 2019

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Mar 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

9.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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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rs750325275

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