rs374299350

Positions:

• chr2-121530909-G-A
• chr2-121530909-G-C
• chr2-121530909-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS2_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.66

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]

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]

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 30180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-121530909-G-A is described in Lovd as [Pathogenic].
• 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/exons	MANE	UniProt
CLASP1	NM_001395891.1	c.196-584C>T		intron_variant		ENST00000696935.1
RNU4ATAC	NR_023343.1	n.30G>A		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	XR_001739683.2	n.608+134G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-584C>T		intron_variant			NM_001395891.1	A2
RNU4ATAC	ENST00000580972.1	n.29G>A		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	ENST00000577914.1	n.354+134G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152180 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000613 AC: 8 AN: 130408 Hom.: 0 AF XY: 0.0000562 AC XY: 4 AN XY: 71180

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 SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000604

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000622 AC: 34 AN: 546738 Hom.: 0 Cov.: 0 AF XY: 0.0000575 AC XY: 17 AN XY: 295832

Gnomad4 AFR exome AF: 0.0000636

Gnomad4 AMR exome AF: 0.0000288

Gnomad4 ASJ exome AF: 0.0000500

Gnomad4 EAS exome AF: 0.000187

Gnomad4 SAS exome AF: 0.0000639

Gnomad4 FIN exome AF: 0.0000301

Gnomad4 NFE exome AF: 0.0000539

Gnomad4 OTH exome AF: 0.0000659

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74470

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000945

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteodysplastic primordial dwarfism, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	Jan 01, 2018	The same individual also harbours another variant g.122288495C>T in the same gene along with this variant as compound heterozygote -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 08, 2011	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 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 (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	17
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

Other links and lift over

dbSNP: rs374299350; hg19: chr2-122288485;