rs575472572

Variant names:

• chr2-121530934-G-A
• rs575472572
• NM_001395891.1:c.196-609C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-121530934-G-A
• chr2-121530934-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001395891.1(CLASP1):​c.196-609C>T variant causes a intron change. The variant allele was found at a frequency of 0.0000885 in 700,406 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.82

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 7 ACMG points.

• PP5: Variant 2-121530934-G-A is Pathogenic according to our data. Variant chr2-121530934-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-121530934-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLASP1	NM_001395891.1	c.196-609C>T		intron_variant	Intron 2 of 40	ENST00000696935.1	NP_001382820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLASP1	ENST00000696935.1	c.196-609C>T		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000690 AC: 9 AN: 130516 Hom.: 0 AF XY: 0.0000702 AC XY: 5 AN XY: 71232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000603

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.0000894 AC: 49 AN: 548088 Hom.: 0 Cov.: 0 AF XY: 0.0000809 AC XY: 24 AN XY: 296784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000864

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000979

Gnomad4 OTH exome AF: 0.000230

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000110

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteodysplastic primordial dwarfism, type 1 Pathogenic:3

Jun 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0217 - Non-coding variant predicted to affect gene expression of downstream targets. This small nuclear RNA forms part of a spliceosome essential for minor intron splicing (PMID: 26522830). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (P) 0309 - An alternative nucleotide change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygtoes). (N) 0600 - Variant is located in an annotated structure. The variant is in the 5’ stem loop structure (PMID: 12409455, 21474760, 26522830). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in 6 unrelated patients with microcephalic osteodysplastic primordial dwarfism, both as homozygotes and compound heterozygote (PMID: 21474760, 21990275, 22581640, 23794361, 26419500, 27040866) (P) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated reduced splicing activities with this variant (PMID: 21474760). (P) 1101 - Very strong and specific phenotype match. (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

-

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Lowry-Wood syndrome;C1846059:Roifman syndrome;C1859452:Osteodysplastic primordial dwarfism, type 1 Pathogenic:2

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2019

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NR_023343.1:n.55G>A a non coding transcript variant has been observed in the homozygous state or as a compound heterozygous, in trans with another disease-causing variantin association with autosomal recessivemicrocephalic osteodysplastic primordial dwarfism type 1 (MOPD) [MIM#210710][PMID: 27040866; PMID:23794361; PMID: 21474760]. The variant has 0.006% allele frequency in the gnomAD database (9 out of 130,516 heterozygous alleles) indicating this is a rare variant. Based on the available evidence, the variant n.55G>Ais classified as Pathogenic -

not provided Pathogenic:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (rs575472572, gnomAD 0.02%). This variant has been observed in individuals with microcephalic osteodysplastic primordial dwarfism or clinical features of RNU4ATAC-related conditions (PMID: 21474760, 23794361, 27040866, 30214071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30179). Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
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: rs575472572; hg19: chr2-122288510;