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:):

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	Protein	UniProt
CLASP1	NM_001395891.1	c.196-584C>T		intron_variant		ENST00000696935.1	NP_001382820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-584C>T		intron_variant			NM_001395891.1	ENSP00000512981.1

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

Labcorp Genetics (formerly Invitae), Labcorp

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;