rs863225422

chr2-121530927-G-Achr2-121530927-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_001395891.1(CLASP1):c.196-602C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 699,952 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 9.43

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_benign. Variant got -4 ACMG points.

• PP5: Variant 2-121530927-G-A is Pathogenic according to our data. Variant chr2-121530927-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218085.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=1, Uncertain_significance=1}. Variant chr2-121530927-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLASP1	NM_001395891.1	c.196-602C>T		intron_variant		ENST00000696935.1
RNU4ATAC	NR_023343.1	n.48G>A		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	XR_001739683.2	n.608+152G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-602C>T		intron_variant			NM_001395891.1	A2
RNU4ATAC	ENST00000580972.1	n.47G>A		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	ENST00000577914.1	n.354+152G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000460 AC: 6 AN: 130500 Hom.: 0 AF XY: 0.0000421 AC XY: 3 AN XY: 71230

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000603

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 63 AN: 547650 Hom.: 0 Cov.: 0 AF XY: 0.000135 AC XY: 40 AN XY: 296500

Gnomad4 AFR exome AF: 0.0000636

Gnomad4 AMR exome AF: 0.0000288

Gnomad4 ASJ exome AF: 0.0000500

Gnomad4 EAS exome AF: 0.0000312

Gnomad4 SAS exome AF: 0.0000798

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.0000658

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2023	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 (no rsID available, gnomAD 0.02%). This variant has been observed in individual(s) with RNU4ATAC-related conditions and/or Roifman syndrome (PMID: 26522830; Invitae). 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: 218085). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Functional studies have shown that this variant disrupts ncRNA splicing (PMID: 32628740). 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). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Roifman syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 20, 2018	- -

RNU4ATAC-related spliceosomopathies Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 31, 2020

The RNU4ATAC n.48G>A variant is a single nucleotide variant in a non-coding region which impacts the U4atac snRNA. The n.48G>A variant is reported in a compound heterozygous state in one individual with Roifman syndrome (Merico et al. 2015). Additionally, the n.48G>A variant is reported in a compound heterozygous state in a second individual with Roifman syndrome in a submission from the Undiagnosed Disease Network (UDN) to the ClinVar database (Landrum et al. 2018). Although not described in the published literature, additional information about this child is available on the UDN website (https://undiagnosed.hms.harvard.edu/participants/participant-127/ ). In both available cases, the n.48G>A variant was reported in trans with the n.13C>T variant. The n.48G>A variant is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. It is located in the kink-turn motif of the 5' stem loop of U4atac snRNA, which interacts with the human NHP2L1 protein during assembly of the minor spliceosome. While the consequences of the n.48G>A variant have not been evaluated experimentally, other variants in the kink-turn motif of the 5' stem loop and observed in individuals with Taybi Linder syndrome have been shown to impair binding to the NHP2L1 protein and minor spliceosome function (Jafarifar et al. 2014; Merico et al. 2015). Based on the collective evidence, the n.48G>A variant is classified as likely pathogenic for RNU4ATAC-related spliceosomopathies. -

Osteodysplastic primordial dwarfism, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

Lowry-Wood syndrome;C1846059:Roifman syndrome;C1859452:Osteodysplastic primordial dwarfism, type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 09, 2022

- -

Lowry-Wood syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
Cadd	Benign	19
Dann	Benign	0.94

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: rs863225422; hg19: chr2-122288503;