chr9-35657872-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NR_003051.4(RMRP):n.148G>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000371 in 700,354 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 Pathogenic (★★).
Frequency
Consequence
NR_003051.4 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RMRP | NR_003051.4 | n.148G>A | non_coding_transcript_exon_variant | Exon 1 of 1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RMRP | ENST00000363046.1 | n.146G>A | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152260Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000460 AC: 6AN: 130490Hom.: 0 AF XY: 0.0000281 AC XY: 2AN XY: 71222
GnomAD4 exome AF: 0.0000365 AC: 20AN: 548094Hom.: 0 Cov.: 0 AF XY: 0.0000337 AC XY: 10AN XY: 296792
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152260Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74392
ClinVar
Submissions by phenotype
Metaphyseal chondrodysplasia, McKusick type Pathogenic:2
Variant summary: RMRP n.147G>A involves the alteration of a conserved nucleotide. The variant allele was found at a frequency of 4.6e-05 in 130490 control chromosomes (gnomAD). This variant is also known as 146G>A. n.147G>A has been reported in the literature in multiple affected individuals (e.g. Ridanpaa_2002, Kavadas_2008, Bordon_2010, Ip_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant to have a mild effect on rRNA and mRNA cleavage activity and to be associated with a mild phenotype (Thiel_2007). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3), and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Anauxetic dysplasia Pathogenic:1
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 (rs753874439, gnomAD 0.01%). This variant has been observed in individual(s) with RMRP-related conditions (PMID: 12107819, 16244706, 18804272; internal data). This variant is also known as 146G>A. ClinVar contains an entry for this variant (Variation ID: 379208). Studies have shown that this variant alters RMRP gene expression (PMID: 17701897). 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
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not provided Pathogenic:1
The r.147 G>A variant has been reported previously as r.146 G>A in association with cartilage-hair hypoplasia (CHH), a disease with variable expressivity, which can present with defective cellular immunity presenting as a SCID phenotype (Thiel et al., 2007; Ridanpää et al., 2002). In vitro functional studiesdemonstrated that the c.147 G>A variant had the least effect on rRNA cleavage activity, which may explain why it is associated with a milder phenotype (Thiel et al., 2007). We interpret this variant as pathogenic. -
Cartilage-Hair Hypoplasia-Anauxetic Dysplasia Spectrum Disorders Pathogenic:1
The RMRP n.147G>A variant, which is also referred to as n.146G>A, is a single nucleotide substitution within the transcribed region that has been reported in a homozygous state in one individual with cartilage-hair hypoplasia (CHH) and in a compound heterozygous state in five unrelated individuals with a diagnosis of or features consistent with CHH (Ridanpää et al. 2002; Bonafé et al. 2005; Kavadas et al. 2008; Türkkani-Asal et al. 2009). The n.147G>A variant is reported at a frequency of 0.000046 in the European (non-Finnish) population of the Genome Aggregation Database. It affects a highly conserved nucleotide and is expected to disrupt the hairpin structure topology. In vitro assays in human fibroblasts have shown that n.147G>A results in a mild reduction of mRNA cleavage activity (~5% less than wildtype) and a slightly larger reduction in rRNA cleavage activity (~20-25% less than wildtype) (Thiel et al. 2007). Based on the collective evidence, the n.147G>A variant is classified as pathogenic for cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at