2-121530932-C-T

Position:

chr2-121530932-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001395891.1(CLASP1):c.196-607G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 700,266 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 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CLASP1
NM_001395891.1 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.82

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_benign. Variant got -1 ACMG points.

PP5

Variant 2-121530932-C-T is Pathogenic according to our data. Variant chr2-121530932-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 692041.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chr2-121530932-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28). . 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	Effect	#exon/exons	MANE	Protein
CLASP1	NM_001395891.1 linkuse as main transcript	c.196-607G>A	intron_variant		ENST00000696935.1	NP_001382820.1
RNU4ATAC	NR_023343.1 linkuse as main transcript	n.53C>T	non_coding_transcript_exon_variant	1/1
CLASP1-AS1	XR_001739683.2 linkuse as main transcript	n.608+157C>T	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLASP1	ENST00000696935.1 linkuse as main transcript	c.196-607G>A	intron_variant			NM_001395891.1	ENSP00000512981	A2
RNU4ATAC	ENST00000580972.1 linkuse as main transcript	n.52C>T	non_coding_transcript_exon_variant	1/1
CLASP1-AS1	ENST00000577914.1 linkuse as main transcript	n.354+157C>T	intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

130510

Hom.:

AF XY:

0.000183

AC XY:

AN XY:

71230

show subpopulations

Gnomad AFR exome

AF:

0.000164

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000958

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

AN:

548074

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

296768

show subpopulations

Gnomad4 AFR exome

AF:

0.0000636

Gnomad4 AMR exome

AF:

0.000375

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000623

Gnomad4 SAS exome

AF:

0.0000638

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000145

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000181

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2022	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 (rs180755563, gnomAD 0.04%). This variant has been observed in individual(s) with Lowry-Wood syndrome (PMID: 30368667). ClinVar contains an entry for this variant (Variation ID: 692041). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	RNU4ATAC: PM3:Strong, PM1, PM5, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2024	Located in the critical region of the 5' stem-loop (PMID: 26522830); Changes the Watson-Crick match to a wobble base pair at a position where a Watson-Crick match is not conserved, which is not expected to affect the secondary structure/function; Located in a stem of the RNU4ATAC non-coding RNA; This variant is associated with the following publications: (PMID: 30368667, 21474760, 32628740, Alomrani 2022[Review]) -

Lowry-Wood syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 11, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 16, 2018	This variant occurs in an element of major importance for splicing in the 5' Stem-loop critical region of the snRNA molecule and is therefore predicted to disrupt minor intron splicing activity (PMID: 26522830). A different nucleotide change as this position was previously reported in a compound heterozygous change in a patient with microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) (PMID: 21474761). The variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. This variant was detected in trans with another CLASP1 variant classified as likely pathogenic . Based on the available evidence the variant is classified as Likely Pathogenic. -

Osteodysplastic primordial dwarfism, type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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