chr2-121531003-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The ENST00000580972.2(RNU4ATAC):n.124G>A variant causes a non coding transcript exon 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

RNU4ATAC
ENST00000580972.2 non_coding_transcript_exon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.56

Publications

3 publications found

Variant links:

Genes affected

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]

RNU4ATAC links:

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]

CLASP1 links:

CLASP1-AS1 (HGNC:55328): (CLASP1 antisense RNA 1)

CLASP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000580972.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RNU4ATAC	NR_023343.3	MANE Select	n.124G>A	non_coding_transcript_exon	Exon 1 of 1
CLASP1	NM_001395891.1	MANE Select	c.196-678C>T	intron	N/A	NP_001382820.1
CLASP1	NM_015282.3		c.196-678C>T	intron	N/A	NP_056097.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RNU4ATAC	ENST00000580972.2	TSL:6 MANE Select	n.124G>A	non_coding_transcript_exon	Exon 1 of 1
CLASP1	ENST00000696935.1	MANE Select	c.196-678C>T	intron	N/A	ENSP00000512981.1
CLASP1	ENST00000263710.8	TSL:5	c.196-678C>T	intron	N/A	ENSP00000263710.4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

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:

AN:

130472

AF XY:

0.0000562

show subpopulations

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:

AN:

548016

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

296748

show subpopulations

African (AFR)

AF:

0.000254

AC:

AN:

15726

American (AMR)

AF:

0.0000288

AC:

AN:

34706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20024

East Asian (EAS)

AF:

0.0000623

AC:

AN:

32098

South Asian (SAS)

AF:

0.0000160

AC:

AN:

62676

European-Finnish (FIN)

AF:

0.0000603

AC:

AN:

33186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2442

European-Non Finnish (NFE)

AF:

0.0000253

AC:

AN:

316752

Other (OTH)

AF:

0.00

AC:

AN:

30406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41528

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Roifman syndrome

Pathogenic:2

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.

Jan 27, 2022

Undiagnosed Diseases Network, NIH

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinal disorders

Pathogenic:1

Sep 04, 2025

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_moderate, PS3_moderate, PM3_supporting, PP4_supporting

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

7.6

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over