rs727502778
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The 9-35658020-C-CGTCCTCAGCTTCACAGA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 688,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000054 ( 0 hom. )
Consequence
RMRP
NR_003051.3 upstream_gene
NR_003051.3 upstream_gene
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -12.3
Genes affected
RMRP (HGNC:10031): (RNA component of mitochondrial RNA processing endoribonuclease) This gene encodes the RNA component of mitochondrial RNA processing endoribonuclease, which cleaves mitochondrial RNA at a priming site of mitochondrial DNA replication. This RNA also interacts with the telomerase reverse transcriptase catalytic subunit to form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase activity and produces double-stranded RNAs that can be processed into small interfering RNA. Mutations in this gene are associated with cartilage-hair hypoplasia.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 9-35658020-C-CGTCCTCAGCTTCACAGA is Pathogenic according to our data. Variant chr9-35658020-C-CGTCCTCAGCTTCACAGA is described in ClinVar as [Pathogenic]. Clinvar id is 14214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RMRP | NR_003051.3 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RMRP | ENST00000363046.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152094Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000314 AC: 4AN: 127388Hom.: 0 AF XY: 0.0000287 AC XY: 2AN XY: 69588
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GnomAD4 exome AF: 0.0000540 AC: 29AN: 536904Hom.: 0 Cov.: 0 AF XY: 0.0000415 AC XY: 12AN XY: 289060
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152094Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74308
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Metaphyseal chondrodysplasia, McKusick type Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2018 | Variant summary: RMRP n.-19_-3dup17 (also known as r.-19_-3dup17) variant involves the duplication of 17 nucleotides in the promoter region of RMRP, which is located between the TATA box (-33 to -25) and the transcription initiation site. The variant allele was found at a frequency of 3.3e-05 in 153424 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (3.3e-05 vs 0.0072), allowing no conclusion about variant significance. n.-19_-3dup17 has been reported in the literature in at least two individuals affected with Cartilage-Hair Hypoplasia in compound heterozygous state (Ridanpaa_2001, Bonafa_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, variant n.-20_-19insTCTGTGAAGCTGGGGAC (rs727502779) that resembles to our variant of interest with one nucleotide difference (the 13th nt) has been reported in CHH patient and the expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene (Nakashima_RMRP_AJMG_2003). One reputable database, OMIM, submitted clinical-significance assessments for this variant to ClinVar and classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 26, 2001 | - - |
Anauxetic dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs727502778, gnomAD 0.009%). This variant has been observed in individuals with cartilage-hair hypoplasia (PMID: 11207361). Other insertions and duplications immediately upstream of the coding sequence have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16244706, 11207361, 12107819). This variant is also known as dupTCTGTGAAGCTGAGGAC at -3. ClinVar contains an entry for this variant (Variation ID: 14214). While functional studies for this variant have not been reported, experimental analyses using patient derived cells, as well as in vitro transfection studies, have shown that promoter insertions result in silencing of RMRP transcription and reduced expression of the gene product (PMID: 11207361, 16254002). For these reasons, this variant has been classified as Pathogenic. - |
Metaphyseal chondrodysplasia, McKusick type;C1834821:Metaphyseal dysplasia without hypotrichosis;C4551965:Anauxetic dysplasia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 19, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2023 | Published functional studies demonstrate that this variant leads to a loss of RMRP expression (Nakashima et al., 2003); Duplication variants in the promoter region disrupt RNA folding/structure; Also known as r.-20_-4dup17; This variant is associated with the following publications: (PMID: 33726816, 11207361, 14608646) - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at