chr9-35658019-A-ACGTCCTCAGCTTC

Variant names:

• chr9-35658019-A-ACGTCCTCAGCTTC
• rs1554651400
• ENST00000363046.2:n.-1_1insGAAGCTGAGGACG

Variant summary

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

The ENST00000363046.2(RMRP):​n.-1_1insGAAGCTGAGGACG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 537,812 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: 0.0000037 (0 hom.)
• Consequence: RMRP ENST00000363046.2 upstream_gene
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.84
• 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 9-35658019-A-ACGTCCTCAGCTTC is Pathogenic according to our data. Variant chr9-35658019-A-ACGTCCTCAGCTTC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 632968.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.-1_1insGAAGCTGAGGACG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.2	n.-1_1insGAAGCTGAGGACG		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000372 AC: 2 AN: 537812 Hom.: 0 Cov.: 0 AF XY: 0.00000345 AC XY: 1 AN XY: 289610

African (AFR) AF: 0.00 AC: 0 AN: 15522

American (AMR) AF: 0.00 AC: 0 AN: 34320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19792

East Asian (EAS) AF: 0.00 AC: 0 AN: 31780

South Asian (SAS) AF: 0.00 AC: 0 AN: 62350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2404

European-Non Finnish (NFE) AF: 0.00000648 AC: 2 AN: 308658

Other (OTH) AF: 0.00 AC: 0 AN: 29910

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:1

Nov 15, 2018

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.-14_-2dup13 variant 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. Multiple duplication variants in this promoter region have been reported pathogenic (internally and in HGMD). The variant was absent in 119274 control chromosomes (gnomAD). To our knowledge, no occurrence of n.-14_-2dup13 in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8

Splicing

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

Other links and lift over

dbSNP: rs1554651400; hg19: chr9-35658016;