chr2-121530909-G-A

Variant names:

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.196-584C>T variant causes a intron change. The variant allele was found at a frequency of 0.0000601 in 699,036 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 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

CLASP1
NM_001395891.1 intron

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.66

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_pathogenic. The variant received 6 ACMG points.

PP5

Variant 2-121530909-G-A is Pathogenic according to our data. Variant chr2-121530909-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 30180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 8 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.196-584C>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.196-584C>T		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1		A0A8V8TLP7

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000613

AC:

AN:

130408

AF XY:

0.0000562

show subpopulations

Gnomad AFR exome

AF:

0.000164

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000192

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000604

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000622

AC:

AN:

546738

Hom.:

Cov.:

AF XY:

0.0000575

AC XY:

AN XY:

295832

show subpopulations

African (AFR)

AF:

0.0000636

AC:

AN:

15718

American (AMR)

AF:

0.0000288

AC:

AN:

34676

Ashkenazi Jewish (ASJ)

AF:

0.0000500

AC:

AN:

19998

East Asian (EAS)

AF:

0.000187

AC:

AN:

32064

South Asian (SAS)

AF:

0.0000639

AC:

AN:

62640

European-Finnish (FIN)

AF:

0.0000301

AC:

AN:

33180

Middle Eastern (MID)

AF:

0.000410

AC:

AN:

2440

European-Non Finnish (NFE)

AF:

0.0000539

AC:

AN:

315658

Other (OTH)

AF:

0.0000659

AC:

AN:

30364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15304

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:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000945

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteodysplastic primordial dwarfism, type 1

Pathogenic:2

Jan 01, 2018

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The same individual also harbours another variant g.122288495C>T in the same gene along with this variant as compound heterozygote -

Apr 08, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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 (rs374299350, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of microcephalic osteodysplastic primordial dwarfism type 1 (PMID: 21474760). 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: 30180). Functional studies have shown that this variant disrupts ncRNA function (PMID: 21474760). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=6/94

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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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