rs199476103

Positions:

• chr9-35657948-T-C
• chr9-35657948-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NR_003051.3(RMRP):​n.71A>G variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00117 in 700,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: RMRP NR_003051.3 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 9-35657948-T-C is Pathogenic according to our data. Variant chr9-35657948-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35657948-T-C is described in Lovd as [Pathogenic]. Variant chr9-35657948-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMRP	NR_003051.3	n.71A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMRP	ENST00000363046.1	n.70A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000874 AC: 114 AN: 130486 Hom.: 0 AF XY: 0.000842 AC XY: 60 AN XY: 71220

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000536

Gnomad FIN exome AF: 0.00854

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.00108 AC: 592 AN: 548096 Hom.: 2 Cov.: 0 AF XY: 0.000991 AC XY: 294 AN XY: 296794

Gnomad4 AFR exome AF: 0.000254

Gnomad4 AMR exome AF: 0.000634

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000431

Gnomad4 FIN exome AF: 0.00889

Gnomad4 NFE exome AF: 0.000676

Gnomad4 OTH exome AF: 0.000986

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.00175 AC XY: 130 AN XY: 74478

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00914

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.00100

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2019	NR_003051.3(RMRP):c.71A>G is classified as pathogenic in the context of cartilage-hair hypoplasia. Sources cited for classification include the following: PMID 16838329, 12107819 and 17701897. Classification of NR_003051.3(RMRP):c.71A>G is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cartilage-hair hypoplasia (MIM# 250250). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Significant, even intrafamilial phenotypic heterogeneity has been reported (PMID: 18804272, 8444246). (I) 0217 - Non-coding variant with known effect. Site directed mutagenesis and transfection to human fibroblasts showed that this variant impaired mildly the endonucleolytic cleavage activity of ITS-1-5.8S rRNA junction site but caused significant decrease of cyclin B2 mRNA cleavage activity (PMID: 17701897). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 350 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is the most common variant in Amish and Finnish patients with cartilage-hair hypoplasia and has been reported as pathogenic in homozygous and compound heterozygous individuals (ClinVar, PMID: 12107819). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Mar 15, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 14, 2023	This variant was identified as compound heterozygous with NR_003051.3:n.119A>G._x000D_ Criteria applied: PS3, PM3_STR -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2019	Variant summary: RMRP n.71A>G (noncoding transcript variant; legacy name 70A>G) is a comon pathogenic founder mutation. The variant allele was found at a frequency of 0.00087 in 130486 control chromosomes (gnomAD). This frequency does not exceed the expected maximal pathogenic allele frequency estimated for pathogenic variants in RMRP (0.0072). n.71A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cartilage-Hair Hypoplasia (CHH; e.g. Ridanpaa_2001). These data indicate that the variant is very likely to be associated with disease. n.71A>G has been reported to impair cleavage of both 5.8S rRNA and cyclin B2 mRNA in the literature (e.g. Hermanns_2005, Thiel_2007). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014). All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Sep 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	RMRP: PP1:Strong, PS4, PM1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2016	The RMRP gene is not translated and codes for the RNA component of a mitochondrial RNA processing endoribonuclease. The r.(71 a>g) variant has been published previously in association with cartilage-hair hypoplasia (CHH) (Ridanpaa et al., 2001; Kainulainen et al., 2014). The r.(71 a>g) variant is the most common pathogenic variant in the RMRP gene, and in the Finnish population the carrier frequency for this variant has been estimated to be as high as 1 in 76 (Sulisalo et al., 1994). This substitution occurs at a position that is conserved across species. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing (Thiel et al., 2007; Hermanns et al., 2005). Therefore, we consider this variant to be pathogenic. -

Metaphyseal dysplasia without hypotrichosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NR_003051.3:n.71A>G in the RMRP gene has an allele frequency of 0.009 in European (Finnish) subpopulation in the gnomAD database. This variant also known as 70A>G in literatures, has been reported in 4/22 Cartilage-Hair Hypoplasia patients in a homozygous state and also in in compound heterozygous constellation with the transversion 262C>G in two sibs and in an unrelated patient and a compound heterozygote of the 70A>G mutant allele and the ( 14_20dup) promoter duplication(PMID: 16838329). This sequence change occurs in the RMRP gene, which encodes the RNA component of the RNase mitochondrial RNA processing (MRP) complex and does not result in a protein product. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing ( PMID: 17701897; 16838329). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PP4. -

Anauxetic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

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 (rs199476103, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16097009, 16838329). It is commonly reported in individuals of Amish ancestry (PMID: 8034306, 12888988). This variant is also known as g.70A>G. ClinVar contains an entry for this variant (Variation ID: 14208). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant is located in a highly conserved P3 domain involved mainly in mRNA cleavage and have been reported to cause impaired cleavage of both 5.8S rRNA and cyclin B2 mRNA in transfected human fibroblast cells (PMID: 10026268, 11207361, 17701897). 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 23, 2022

- -

RMRP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2023

The RMRP n.71A>G is a noncoding alteration. This variant, also known as n.70A>G in the literature, was reported in the homozygous or compound heterozygous state in numerous individuals with RMRP-associated disorders (Ridanpää et al. 2001. PubMed ID: 11207361; Thiel et al. 2007. PubMed ID: 17701897). Functional studies showed that the n.71A>G substitution results in impaired cleavage activity and aberrant ribosomal processing (Hermanns et al. 2005. PubMed ID: 16254002; Thiel et al. 2007. PubMed ID: 17701897). This variant is reported in 0.87% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476103; hg19: chr9-35657945;