Variant 9-35658029-C-CTTCACAGAGTAGT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The 9-35658029-C-CTTCACAGAGTAGT variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 685,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RMRP
NR_003051.3 upstream_gene

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -4.18

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-35658029-C-CTTCACAGAGTAGT is Pathogenic according to our data. Variant chr9-35658029-C-CTTCACAGAGTAGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMRP	NR_003051.3 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMRP	ENST00000363046.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000238

AC:

AN:

125872

Hom.:

AF XY:

0.0000436

AC XY:

AN XY:

68768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000188

AC:

AN:

533082

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

286548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000968

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000982

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2021	Variant summary: RMRP n.-24_-12dup13 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. The variant allele was found at a frequency of 2.1e-05 in 239252 control chromosomes (gnomAD v2.1 and v3.1 datasets). The variant, n.-24_-12dup13, has been reported in the literature in a compound heterozygous patient affected with Omenn syndrome (Kavadas_2008). To our knowledge, no experimental evidence demonstrating an impact on RNA function has been reported. However, many other insertions or duplications 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). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Anauxetic dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

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 (rs781730798, gnomAD 0.01%). 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). ClinVar contains an entry for this variant (Variation ID: 551654). 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. -

RMRP-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2023

The RMRP n.-24_-12dup13 variant is predicted to result in an in-frame duplication (Non-Coding). This variant was reported in an individual with cartilage-hair hypoplasia (reported as g.-26_-14dup in McCann et al. 2013. PubMed ID: 24217815). Other insertions and duplications immediately upstream of the RMRP coding sequence have been reported in individuals with cartilage-hair hypoplasia (Kavadas et al. 2008. PubMed ID: 18804272; Thiel et al. 2011. PubMed ID: 21396580; Ridanpää et al. 2001. PubMed ID: 11207361; Bonafé et al. 2005. PubMed ID: 16244706). This variant has interpretations of pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/465207/) and has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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