9-35658029-C-CTTCACAGAGTAGTTCACAGAGTAGTTCACAGAGTAG

Variant names:

• chr9-35658029-C-CTTCACAGAGTAGTTCACAGAGTAGTTCACAGAGTAG
• rs781730798
• ENST00000363046.2:n.-11_-10insCTACTCTGTGAACTACTCTGTGAACTACTCTGTGAA

Variant summary

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

The ENST00000363046.2(RMRP):​n.-11_-10insCTACTCTGTGAACTACTCTGTGAACTACTCTGTGAA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RMRP ENST00000363046.2 upstream_gene
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -4.18
• 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 9-35658029-C-CTTCACAGAGTAGTTCACAGAGTAGTTCACAGAGTAG is Pathogenic according to our data. Variant chr9-35658029-C-CTTCACAGAGTAGTTCACAGAGTAGTTCACAGAGTAG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1066082.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.-11_-10insCTACTCTGTGAACTACTCTGTGAACTACTCTGTGAA		upstream_gene_variant		ENST00000363046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.2	n.-11_-10insCTACTCTGTGAACTACTCTGTGAACTACTCTGTGAA		upstream_gene_variant		6	NR_003051.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anauxetic dysplasia Pathogenic:1

Jul 15, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. 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		-4.2

Splicing

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

Other links and lift over

dbSNP: rs781730798; hg19: chr9-35658026;