9-35658024-C-CTCAGCTTCACAGAGTAG

Variant names:

• chr9-35658024-C-CTCAGCTTCACAGAGTAG
• rs920074067
• ENST00000363046.2:n.-6_-5insCTACTCTGTGAAGCTGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP5_Moderate

The NR_003051.4(RMRP):​n.-6_-5insCTACTCTGTGAAGCTGA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 534,984 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 (★). ClinVar reports functional evidence for this variant: "SCV002237215: 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).". The gene RMRP is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -11.8
• 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: G2P, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for RMRP are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002237215: 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).
• PP5: Variant 9-35658024-C-CTCAGCTTCACAGAGTAG is Pathogenic according to our data. Variant chr9-35658024-C-CTCAGCTTCACAGAGTAG is described in ClinVar as Pathogenic. ClinVar VariationId is 554699.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_003051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.-6_-5insCTACTCTGTGAAGCTGA		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.-6_-5insCTACTCTGTGAAGCTGA		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000131 AC: 7 AN: 534984 Hom.: 0 Cov.: 0 AF XY: 0.0000104 AC XY: 3 AN XY: 287754

African (AFR) AF: 0.00 AC: 0 AN: 15438

American (AMR) AF: 0.00 AC: 0 AN: 34032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19650

East Asian (EAS) AF: 0.00 AC: 0 AN: 31748

South Asian (SAS) AF: 0.0000161 AC: 1 AN: 62170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2396

European-Non Finnish (NFE) AF: 0.0000196 AC: 6 AN: 306728

Other (OTH) AF: 0.00 AC: 0 AN: 29784

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Anauxetic dysplasia (1)
1	-	-	Metaphyseal chondrodysplasia, McKusick type (1)

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: rs920074067; hg19: chr9-35658021;