VCV000030179.10 - ClinVar

NR_023343.3(RNU4ATAC):n.55G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NR_023343.3(RNU4ATAC):n.55G>A

Variation ID: 30179 Accession: VCV000030179.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q14.2 2: 121530934 (GRCh38) [ NCBI UCSC ] 2: 122288510 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 20, 2015	Feb 14, 2024	Nov 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001395891.1:c.196-609C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001142273.2:c.196-609C>T		intron variant
NM_001142274.2:c.196-609C>T		intron variant
NM_001207051.2:c.196-609C>T		intron variant
NM_001378003.1:c.196-609C>T		intron variant
NM_001378004.1:c.196-609C>T		intron variant
NM_001378005.1:c.196-609C>T		intron variant
NM_015282.3:c.196-609C>T		intron variant
NR_023343.3:n.55G>A
NC_000002.12:g.121530934G>A
NC_000002.11:g.122288510G>A
NG_029832.1:g.5055G>A
LRG_1202:g.5055G>A
LRG_1202t1:n.55G>A

... more HGVS ... less HGVS

Protein change

Other names

55G-A

Canonical SPDI

NC_000002.12:121530933:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00009

Trans-Omics for Precision Medicine (TOPMed) 0.00011

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA129001 OMIM: 601428.0002 dbSNP: rs575472572 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 21474760 Fig. 1 to determine the location of this allele on the current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CLASP1		No evidence available	No evidence available	GRCh38 GRCh37	65	334
RNU4ATAC		-	-	GRCh38 GRCh37	1	267

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Osteodysplastic primordial dwarfism, type 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 11, 2020	RCV000023097.8
Intellectual disability Short stature	Pathogenic (1)	criteria provided, single submitter	May 24, 2019	RCV001263287.2
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 24, 2023	RCV001852008.5
Lowry-Wood syndrome Osteodysplastic primordial dwarfism, type 1 Roifman syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 22, 2022	RCV002490406.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 24, 2019)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Intellectual disability Short stature (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001441325.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Publications: PubMed (3) PubMed: 27040866‚ 23794361‚ 21474760 Comment: 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 … (more) 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 (less) Zygosity: Compound Heterozygote Secondary finding: no
Pathogenic (Apr 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteodysplastic primordial dwarfism, type 1 Lowry-Wood syndrome Roifman syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002779417.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Osteodysplastic primordial dwarfism, type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences Accession: SCV001451937.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Clinical Features: Microcephaly (present) , Seizure (present) , Dry skin (present) , Global developmental delay (present) , Simplified gyral pattern (present) , Corpus callosum, agenesis of (present) Zygosity: Compound Heterozygote Age: 0-9 years Sex: female Ethnicity/Population group: North Indian Geographic origin: India
Pathogenic (Jun 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteodysplastic primordial dwarfism, type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768853.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 12409455‚ 21474760‚ 21990275‚ 22581640‚ 23794361‚ 26419500‚ 26522830‚ 27040866 Comment: 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 … (more) 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 (less)
Pathogenic (Nov 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002246369.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 21474760‚ 23794361‚ 27040866‚ 30214071‚ 32628740‚ 30368667 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 01, 2012)	no assertion criteria provided Method: literature only	MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044388.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2015	Publications: PubMed (2) PubMed: 21474760‚ 22581640 Comment on evidence: In a reportedly nonconsanguineous German family with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 55G-A … (more) In a reportedly nonconsanguineous German family with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 55G-A mutation in the RNU4ATAC gene. This mutation was predicted to disrupt the 5-prime stem loop of this snRNA secondary structure and cause defects in the minor spliceosome. This mutation reduced U12-dependent splicing activity by 90% relative to wildtype. In a brother and sister with MOPD1, born of double consanguineous first-cousin parents, Abdel-Salam et al. (2012) identified homozygosity for the genomic 55G-A mutation in the RNU4ATAC gene. The authors noted that the sibs had a relatively mild MOPD1 phenotype, with developmental milestones only mildly delayed for age; however, both developed high fever and convulsions and died of encephalitis at 18 months and 34 months of age. (less)

Comment:

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

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene.	Benoit-Pilven C	PloS one	2020	PMID: 32628740
Genomic and phenotypic delineation of congenital microcephaly.	Shaheen R	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30214071
Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype.	Shelihan I	Human genetics	2018	PMID: 30368667
Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome.	Putoux A	Clinical genetics	2016	PMID: 27040866
Long-term survival in microcephalic osteodysplastic primordial dwarfism type I: Evaluation of an 18-year-old male with g.55G>A homozygous mutation in RNU4ATAC.	Abdel-Salam GM	American journal of medical genetics. Part A	2016	PMID: 26419500
Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing.	Merico D	Nature communications	2015	PMID: 26522830
Further delineation of the clinical spectrum in RNU4ATAC related microcephalic osteodysplastic primordial dwarfism type I.	Abdel-Salam GM	American journal of medical genetics. Part A	2013	PMID: 23794361
Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I.	Abdel-Salam GM	American journal of medical genetics. Part A	2012	PMID: 22581640
A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder.	Abdel-Salam GM	American journal of medical genetics. Part A	2011	PMID: 21990275
Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I.	He H	Science (New York, N.Y.)	2011	PMID: 21474760
Domains of human U4atac snRNA required for U12-dependent splicing in vivo.	Shukla GC	Nucleic acids research	2002	PMID: 12409455
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Text-mined citations for rs575472572 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NR_023343.3(RNU4ATAC):n.55G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs575472572 ...