rs551450545
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NR_003051.3(RMRP):n.243A>G variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000861 in 696,526 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 0.000092 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000085 ( 0 hom. )
Consequence
RMRP
NR_003051.3 non_coding_transcript_exon
NR_003051.3 non_coding_transcript_exon
Scores
2
Clinical Significance
Conservation
PhyloP100: 7.16
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-35657776-T-C is Pathogenic according to our data. Variant chr9-35657776-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35657776-T-C is described in Lovd as [Likely_pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.14). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RMRP | NR_003051.3 | n.243A>G | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RMRP | ENST00000363046.1 | n.242A>G | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152212Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000116 AC: 15AN: 128784Hom.: 0 AF XY: 0.000128 AC XY: 9AN XY: 70378
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GnomAD4 exome AF: 0.0000845 AC: 46AN: 544314Hom.: 0 Cov.: 0 AF XY: 0.0000952 AC XY: 28AN XY: 294072
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152212Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Metaphyseal chondrodysplasia, McKusick type Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 18, 2021 | Variant summary: RMRP n.243A>G (also known as 242A>G) involves the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 128784 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.0001 vs 0.0072), allowing no conclusion about variant significance. The variant, n.243A>G, has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (e.g. Ridanpaa_2002, Bonafe_2005, Kavadas_2008, Ip_2015, Faitelson_2015, Sathishkumar_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Anauxetic dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 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 (rs551450545, gnomAD 0.03%). This variant has been observed in individual(s) with cartilage hair hypoplasia (PMID: 12107819, 18804272, 25663137, 29744913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 242A>G and 242G. ClinVar contains an entry for this variant (Variation ID: 487451). 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
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 23, 2021 | - - |
Computational scores
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at