rs188343279

chr2-121530930-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PP5_Very_Strong BP4 BS2

The NM_001395891.1(CLASP1):c.196-605C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 700,358 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 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.51

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 Uncertain_significance. Variant got 3 ACMG points.

• PP5: Variant 2-121530930-G-A is Pathogenic according to our data. Variant chr2-121530930-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-121530930-G-A is described in Lovd as [Pathogenic]. Variant chr2-121530930-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLASP1	NM_001395891.1	c.196-605C>T		intron_variant		ENST00000696935.1
RNU4ATAC	NR_023343.1	n.51G>A		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	XR_001739683.2	n.608+155G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-605C>T		intron_variant			NM_001395891.1	A2
RNU4ATAC	ENST00000580972.1	n.50G>A		non_coding_transcript_exon_variant	1/1
CLASP1-AS1	ENST00000577914.1	n.354+155G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000429 AC: 56 AN: 130510 Hom.: 0 AF XY: 0.000407 AC XY: 29 AN XY: 71230

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000575

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000383

Gnomad SAS exome AF: 0.000536

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.000402

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000494 AC: 271 AN: 548072 Hom.: 0 Cov.: 0 AF XY: 0.000522 AC XY: 155 AN XY: 296768

Gnomad4 AFR exome AF: 0.000191

Gnomad4 AMR exome AF: 0.000519

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000592

Gnomad4 SAS exome AF: 0.000686

Gnomad4 FIN exome AF: 0.000211

Gnomad4 NFE exome AF: 0.000534

Gnomad4 OTH exome AF: 0.000395

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74464

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000317 Hom.: 0

Bravo AF: 0.000536

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	RNU4ATAC: PM3:Very Strong, PS3:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Apr 19, 2023	PS4_MOD, PP1, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2021	The non-coding variant, n.51G>A, has been described in gnomAD with an allele frequency of 0.054% in the South Asian sub-population (dbSNP rsrs181195449). This sequence change is located in the 5' stem loop critical region. The n.51G>A is a known pathogenic sequence change and has been reported in multiple cases with microcephalic osteodysplastic primordial dwarfism either in the homozygous or compound heterozygous state (PMIDs: 21474760, 23794361, 32628740, 29265708, 27312855, 26522830). Functional studies have also demonstrated that this sequence change reduced U12-dependent splicing activity by 90% compared to wildtype (PMID:21474760). Based on this information this variant is being classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 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 (rs188343279, gnomAD 0.07%). This variant has been observed in individual(s) with RNU4ATAC-related conditions (PMID: 21474760, 26522830). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30178). 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). For these reasons, this variant has been classified as Pathogenic. -

Roifman syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2023	Variant summary: RNU4ATAC n.51G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00043 in 130510 control chromosomes. n.51G>A has been reported in the literature in multiple individuals affected with Microcephalic osteodysplastic primordial dwarfism, type I or Roifman Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (He_2012). The following publications have been ascertained in the context of this evaluation (PMID: 21474760, 26522830). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -

Osteodysplastic primordial dwarfism, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2015	- -

RNU4ATAC-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2022

The RNU4ATAC n.51G>A is a noncoding alteration. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with RNU4ATAC-related disorders, and functional studies support its pathogenicity (He et al. 2011. PubMed ID: 21474760; Abdel-Salam et al. 2013. PubMed ID: 23794361; Merico et al. 2015. PubMed ID: 26522830; Farach et al. 2017. PubMed ID: 29265708; Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.063% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288506-G-A). This variant is interpreted as pathogenic. -

Lowry-Wood syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2015

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	18
Dann	Benign	0.91
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: rs188343279; hg19: chr2-122288506;