9-35658025-T-TCAGCTTCACAGAGTAGTACC

Variant names:

• chr9-35658025-T-TCAGCTTCACAGAGTAGTACC
• rs1554651473
• ENST00000363046.2:n.-7_-6insGGTACTACTCTGTGAAGCTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The ENST00000363046.2(RMRP):​n.-7_-6insGGTACTACTCTGTGAAGCTG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 535,124 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: RMRP ENST00000363046.2 upstream_gene
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -6.64
• Publications: 0 publications found

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]

RMRP Gene-Disease associations (from GenCC):

• cartilage-hair hypoplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 9-35658025-T-TCAGCTTCACAGAGTAGTACC is Pathogenic according to our data. Variant chr9-35658025-T-TCAGCTTCACAGAGTAGTACC is described in ClinVar as Pathogenic. ClinVar VariationId is 2123397.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4	n.-7_-6insGGTACTACTCTGTGAAGCTG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.2	n.-7_-6insGGTACTACTCTGTGAAGCTG		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000187 AC: 1 AN: 535124 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 287848

African (AFR) AF: 0.00 AC: 0 AN: 15436

American (AMR) AF: 0.00 AC: 0 AN: 34072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19664

East Asian (EAS) AF: 0.00 AC: 0 AN: 31752

South Asian (SAS) AF: 0.00 AC: 0 AN: 62200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2400

European-Non Finnish (NFE) AF: 0.00000326 AC: 1 AN: 306768

Other (OTH) AF: 0.00 AC: 0 AN: 29788

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anauxetic dysplasia Pathogenic:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). While this particular variant has not been reported in the literature, it is located in the promoter region between the TATA box and the transcription initiation site, and 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 not present in population databases (gnomAD no frequency). This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-6.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554651473; hg19: chr9-35658022;