rs727502778

Variant names:

• chr9-35658020-C-CGTCCTCAGCTTCACAGA
• rs727502778
• ENST00000363046.2:n.-2_-1insTCTGTGAAGCTGAGGAC

Your query was ambiguous. Multiple possible variants found:

• chr9-35658020-C-CGTCCTCAGCTTCACAGA
• chr9-35658020-C-CGTCCTCAGCTTCACAGAGTCCTCAGCTTCACAGA
• chr9-35658020-C-CGTCCTCAGCTTCACAGAGT

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_-1insTCTGTGAAGCTGAGGAC variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 688,998 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: RMRP ENST00000363046.2 upstream_gene
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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-CGTCCTCAGCTTCACAGA is Pathogenic according to our data. Variant chr9-35658020-C-CGTCCTCAGCTTCACAGA is described in ClinVar as Pathogenic. ClinVar VariationId is 14214.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.-2_-1insTCTGTGAAGCTGAGGAC		upstream_gene_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152094 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000314 AC: 4 AN: 127388 AF XY: 0.0000287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000420

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000965

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000416

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 29 AN: 536904 Hom.: 0 Cov.: 0 AF XY: 0.0000415 AC XY: 12 AN XY: 289060

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

American (AMR) AF: 0.0000584 AC: 2 AN: 34230

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

East Asian (EAS) AF: 0.0000315 AC: 1 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: 0.0000844 AC: 26 AN: 308116

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

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152094 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

African (AFR) AF: 0.0000724 AC: 3 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:3

Feb 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RMRP n.-19_-3dup17 (also known as r.-19_-3dup17) variant involves the duplication of 17 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 3.3e-05 in 153424 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (3.3e-05 vs 0.0072), allowing no conclusion about variant significance. n.-19_-3dup17 has been reported in the literature in at least two individuals affected with Cartilage-Hair Hypoplasia in compound heterozygous state (Ridanpaa_2001, Bonafa_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, variant n.-20_-19insTCTGTGAAGCTGGGGAC (rs727502779) that resembles to our variant of interest with one nucleotide difference (the 13th nt) has been reported in CHH patient and the expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene (Nakashima_RMRP_AJMG_2003). One reputable database, OMIM, submitted clinical-significance assessments for this variant to ClinVar and classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 26, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 25, 2024

Laboratorio de Biologia Molecular/Medicina Genomica - IFF/Fiocruz, Instituto Fernandes Figueira, Fundacao Oswaldo Cruz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant n.-18_-2dupTCTGTGAAGCTGAGGAC was identified in a compound heterozygous state with another variant in the transcribed region of RMRP gene in an individual affected with Cartilage-Hair Hypoplasia. This alteration is located within the promoter region of the RMRP gene, which encodes an untranslated RNA. Segregation analysis showed that each of the unaffected parents was heterozygous for one of the two variants. Other insertions and duplications in this region have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders (PMID: 11207361, 21956908, 21396580). This variant involves the duplication of 17 nucleotides between the TATA box and the transcription initiation site and functional studies have shown that this type of alteration result in reduced expression of the RMRP gene (PMIDs: 11207361, 16254002). For these reasons, this variant has been classified as Pathogenic. -

Anauxetic dysplasia Pathogenic:1

Nov 06, 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 (rs727502778, gnomAD 0.009%). This variant has been observed in individuals with cartilage-hair hypoplasia (PMID: 11207361). 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). This variant is also known as dupTCTGTGAAGCTGAGGAC at -3. ClinVar contains an entry for this variant (Variation ID: 14214). 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. -

Metaphyseal chondrodysplasia, McKusick type;C1834821:Metaphyseal dysplasia without hypotrichosis;C4551965:Anauxetic dysplasia 1 Pathogenic:1

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant leads to a loss of RMRP expression (Nakashima et al., 2003); Duplication variants in the promoter region disrupt RNA folding/structure; Also known as r.-20_-4dup17; This variant is associated with the following publications: (PMID: 33726816, 11207361, 14608646) -

Computational scores

Source: dbNSFP v4.3

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;