9-35657948-T-C

Variant names:

• chr9-35657948-T-C
• rs199476103
• ENST00000363046.2:n.72A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS2_Supporting

The ENST00000363046.2(RMRP):​n.72A>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 ENST00000363046.2 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 7.16
• Publications: 12 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 6 ACMG points.

• PP5: Variant 9-35657948-T-C is Pathogenic according to our data. Variant chr9-35657948-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000363046.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.72A>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.72A>G		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.000874 AC: 114 AN: 130486 AF XY: 0.000842

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 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

African (AFR) AF: 0.000254 AC: 4 AN: 15734

American (AMR) AF: 0.000634 AC: 22 AN: 34708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.00 AC: 0 AN: 32104

South Asian (SAS) AF: 0.000431 AC: 27 AN: 62682

European-Finnish (FIN) AF: 0.00889 AC: 295 AN: 33194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2444

European-Non Finnish (NFE) AF: 0.000676 AC: 214 AN: 316790

Other (OTH) AF: 0.000986 AC: 30 AN: 30414

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.00100

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:10

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 14, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous with NR_003051.3:n.119A>G._x000D_ Criteria applied: PS3, PM3_STR

Nov 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 15, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Jun 03, 2021

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 24, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.117%). Predicted Consequence/Location: noncoding transcript variant The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000014208 /PMID: 11207361). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Oct 18, 2019

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.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.

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 05, 2025

Clinical Biomedical Laboratory, Shriners Hospital For Children - Canada

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RMRP encodes an RNA molecule that is not translated into a protein. This variant is rare in the Genome Aggregation Database (v2.1.1) and is not present in homozygous form in that database. The variant is the most common cause of cartilage-hair hypoplasia and has also been reported in individuals who were diagnosed with ‘metaphyseal dysplasia without hypotrichosis’ (PMID: 31413121).

not provided Pathogenic:5

Sep 01, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 18, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RMRP: PM3:Very Strong, PM1:Supporting, PM2:Supporting, PS3:Supporting

Jul 01, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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.

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Anauxetic dysplasia Pathogenic:1

Jan 29, 2025

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 (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 gene product 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

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RMRP-related disorder Pathogenic:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		7.2
PromoterAI		0.021	Neutral

Splicing

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

Other links and lift over

dbSNP: rs199476103; hg19: chr9-35657945;