9-35658020-C-CGTCCTCAGCTTCACAGAGTCCTCAGCTTCACAGA

Variant names:

• chr9-35658020-C-CGTCCTCAGCTTCACAGAGTCCTCAGCTTCACAGA
• rs727502778
• ENST00000363046.2:n.-2_-1insTCTGTGAAGCTGAGGACTCTGTGAAGCTGAGGAC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000363046.2(RMRP):​n.-2_-1insTCTGTGAAGCTGAGGACTCTGTGAAGCTGAGGAC variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 536,904 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: RMRP ENST00000363046.2 upstream_gene
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -12.3
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 9-35658020-C-CGTCCTCAGCTTCACAGAGTCCTCAGCTTCACAGA is Pathogenic according to our data. Variant chr9-35658020-C-CGTCCTCAGCTTCACAGAGTCCTCAGCTTCACAGA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1696063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000363046.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.-2_-1insTCTGTGAAGCTGAGGACTCTGTGAAGCTGAGGAC		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.-2_-1insTCTGTGAAGCTGAGGACTCTGTGAAGCTGAGGAC		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000559 AC: 3 AN: 536904 Hom.: 0 Cov.: 0 AF XY: 0.00000346 AC XY: 1 AN XY: 289060

African (AFR) AF: 0.00 AC: 0 AN: 15486

American (AMR) AF: 0.00 AC: 0 AN: 34230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19712

East Asian (EAS) AF: 0.00 AC: 0 AN: 31782

South Asian (SAS) AF: 0.00 AC: 0 AN: 62268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2398

European-Non Finnish (NFE) AF: 0.00000974 AC: 3 AN: 308116

Other (OTH) AF: 0.00 AC: 0 AN: 29856

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:1

May 25, 2022

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.-19_-3[3] involves the triplication of 17 nucleotides in the promoter region of RMRP, which is located between the TATA box (-33 to -25) and the transcription initiation site. Other insertions, duplications or triplications in the promoter region of RMRP have been classified as pathogenic (internally and in ClinVar). The variant was absent in 127578 control chromosomes (gnomAD). To our knowledge, no occurrence of n.-19_-3[3] in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on RNA function have been reported. However, several other insertions, duplications or triplications 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Anauxetic dysplasia Pathogenic:1

Dec 02, 2023

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 not present in population databases (gnomAD no frequency). 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). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-12

Splicing

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

Other links and lift over

dbSNP: rs727502778; hg19: chr9-35658017;