chr9-35658029-C-CTTCACAGAGTAGT

Variant names:

• chr9-35658029-C-CTTCACAGAGTAGT
• rs781730798
• ENST00000363046.1:n.-13_-12insACTACTCTGTGAA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NR_003051.4(RMRP):​n.-11_-10insACTACTCTGTGAA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 685,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -4.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35658029-C-CTTCACAGAGTAGT is Pathogenic according to our data. Variant chr9-35658029-C-CTTCACAGAGTAGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4	n.-11_-10insACTACTCTGTGAA		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1	n.-13_-12insACTACTCTGTGAA		upstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000238 AC: 3 AN: 125872 Hom.: 0 AF XY: 0.0000436 AC XY: 3 AN XY: 68768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 10 AN: 533082 Hom.: 0 Cov.: 0 AF XY: 0.0000279 AC XY: 8 AN XY: 286548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000968

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000982

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:3

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 03, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RMRP n.-24_-12dup13 involves the duplication of 13 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 2.1e-05 in 239252 control chromosomes (gnomAD v2.1 and v3.1 datasets). The variant, n.-24_-12dup13, has been reported in the literature in a compound heterozygous patient affected with Omenn syndrome (Kavadas_2008). To our knowledge, no experimental evidence demonstrating an impact on RNA function has been reported. However, many other insertions or duplications in the promoter region of RMRP have been reported in affected individuals in the literature (e.g. PMIDs: 21956908, 21396580) and have been demonstrated through functional studies to lead to reduced RMRP transcription (e.g. PMIDs: 11207361, 16254002, 17937437). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Anauxetic dysplasia Pathogenic:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (rs781730798, gnomAD 0.01%). 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). ClinVar contains an entry for this variant (Variation ID: 551654). 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. -

RMRP-related disorder Pathogenic:1

Apr 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RMRP n.-24_-12dup13 variant is predicted to result in an in-frame duplication (Non-Coding). This variant was reported in an individual with cartilage-hair hypoplasia (reported as g.-26_-14dup in McCann et al. 2013. PubMed ID: 24217815). Other insertions and duplications immediately upstream of the RMRP coding sequence have been reported in individuals with cartilage-hair hypoplasia (Kavadas et al. 2008. PubMed ID: 18804272; Thiel et al. 2011. PubMed ID: 21396580; Ridanpää et al. 2001. PubMed ID: 11207361; Bonafé et al. 2005. PubMed ID: 16244706). This variant has interpretations of pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/465207/) and has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs781730798; hg19: chr9-35658026;