9-35658030-T-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NR_003051.4(RMRP):n.-11A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 682,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NR_003051.4 upstream_gene
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RMRP | NR_003051.4 | n.-11A>C | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RMRP | ENST00000363046.1 | n.-13A>C | upstream_gene_variant | 6 |
Frequencies
GnomAD3 genomes AF: 0.00145 AC: 220AN: 152218Hom.: 1 Cov.: 34
GnomAD3 exomes AF: 0.000578 AC: 72AN: 124488Hom.: 0 AF XY: 0.000528 AC XY: 36AN XY: 68130
GnomAD4 exome AF: 0.000305 AC: 162AN: 530596Hom.: 0 Cov.: 0 AF XY: 0.000270 AC XY: 77AN XY: 284938
GnomAD4 genome AF: 0.00146 AC: 223AN: 152336Hom.: 1 Cov.: 34 AF XY: 0.00140 AC XY: 104AN XY: 74486
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: The RMRP variant, n.-12A>C is located in the promoter region and is also referred to as n.-13A>C. Duplications in this region have been classified as pathogenic, although single nucleotide changes have not commonly been classified in this region to be pathogenic. The variant allele was found at a frequency of 0.00067 in 150636 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.00067 vs 0.0072), allowing no conclusion about variant significance. n.-12A>C has been reported in the literature in an individual affected with Cartilage-Hair Hypoplasia, which authors indicate the cause for disease was g.97G>A and g.27G>C. Therefore, this variant was in cis with g.27G>C and assumed to be nonpathogenic by the authors (Cherkaoui Jaouad_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -
not provided Uncertain:1
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Metaphyseal chondrodysplasia, McKusick type Benign:1
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Anauxetic dysplasia Benign:1
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RMRP-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at