rs544312701

Variant names:

• chr2-121531003-G-A
• rs544312701
• NM_001395891.1:c.196-678C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-121531003-G-A
• chr2-121531003-G-C
• chr2-121531003-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS2_Supporting

The NM_001395891.1(CLASP1):​c.196-678C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000371 in 700,188 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: 0.000033 (0 hom.)
• Consequence: CLASP1 NM_001395891.1 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.56
• Publications: 3 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP5: Variant 2-121531003-G-A is Pathogenic according to our data. Variant chr2-121531003-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24). . 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 rank	MANE	Protein	UniProt
CLASP1	NM_001395891.1	c.196-678C>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.196-678C>T		intron_variant	Intron 2 of 40		NM_001395891.1	ENSP00000512981.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000613 AC: 8 AN: 130472 AF XY: 0.0000562

Gnomad AFR exome AF: 0.000329

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000958

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000402

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.0000328 AC: 18 AN: 548016 Hom.: 0 Cov.: 0 AF XY: 0.0000236 AC XY: 7 AN XY: 296748

African (AFR) AF: 0.000254 AC: 4 AN: 15726

American (AMR) AF: 0.0000288 AC: 1 AN: 34706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20024

East Asian (EAS) AF: 0.0000623 AC: 2 AN: 32098

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62676

European-Finnish (FIN) AF: 0.0000603 AC: 2 AN: 33186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2442

European-Non Finnish (NFE) AF: 0.0000253 AC: 8 AN: 316752

Other (OTH) AF: 0.00 AC: 0 AN: 30406

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74406

African (AFR) AF: 0.0000963 AC: 4 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Roifman syndrome Pathogenic:2

Jan 27, 2022

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RNU4ATAC n.124G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 6.1e-05 in 130472 control chromosomes. n.124G>A has been reported in the literature in individuals affected with Microcephalic Osteodysplastic Primordial Dwarfism type I (Putoux_2016, Abdel-Salaam_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence demonstrating a greater than 90% decrease in snRNA (Jafarifar_2014). The following publications have been ascertained in the context of this evaluation (PMID: 22581640, 24865609, 27040866). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Oct 15, 2024

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 (rs544312701, gnomAD 0.02%). This variant has been observed in individual(s) with microcephalic osteodysplastic primordial dwarfism, type I (PMID: 22581640, 27040866). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39443). Functional studies have shown that this variant disrupts ncRNA function (PMID: 24865609) This variant is located within the Sm protein-binding region of the RNU4ATAC RNA, which is important for small nuclear RNA maturation (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. -

Osteodysplastic primordial dwarfism, type 1 Pathogenic:1

Jun 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.92
PhyloP100		7.6
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs544312701; hg19: chr2-122288579;