ENST00000363046.2:n.148G>A

Variant names:

• chr9-35657872-C-T
• rs753874439
• ENST00000363046.2:n.148G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000363046.2(RMRP):​n.148G>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000371 in 700,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: RMRP ENST00000363046.2 non_coding_transcript_exon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.04
• Publications: 3 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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35657872-C-T is Pathogenic according to our data. Variant chr9-35657872-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 379208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27). . Strength limited to SUPPORTING due to the PP5.

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.148G>A		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.148G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152260 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000460 AC: 6 AN: 130490 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000603

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000365 AC: 20 AN: 548094 Hom.: 0 Cov.: 0 AF XY: 0.0000337 AC XY: 10 AN XY: 296792

African (AFR) AF: 0.00 AC: 0 AN: 15734

American (AMR) AF: 0.0000288 AC: 1 AN: 34708

Ashkenazi Jewish (ASJ) AF: 0.0000499 AC: 1 AN: 20026

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

South Asian (SAS) AF: 0.0000638 AC: 4 AN: 62682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33192

Middle Eastern (MID) AF: 0.000409 AC: 1 AN: 2444

European-Non Finnish (NFE) AF: 0.0000379 AC: 12 AN: 316792

Other (OTH) AF: 0.0000329 AC: 1 AN: 30412

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152260 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74392

African (AFR) AF: 0.0000482 AC: 2 AN: 41474

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:2

Mar 31, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jan 20, 2022

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.147G>A involves the alteration of a conserved nucleotide. The variant allele was found at a frequency of 4.6e-05 in 130490 control chromosomes (gnomAD). This variant is also known as 146G>A. n.147G>A has been reported in the literature in multiple affected individuals (e.g. Ridanpaa_2002, Kavadas_2008, Bordon_2010, Ip_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant to have a mild effect on rRNA and mRNA cleavage activity and to be associated with a mild phenotype (Thiel_2007). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3), and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Anauxetic dysplasia Pathogenic:1

Dec 23, 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 (rs753874439, gnomAD 0.01%). This variant has been observed in individual(s) with RMRP-related conditions (PMID: 12107819, 16244706, 18804272; internal data). This variant is also known as 146G>A. ClinVar contains an entry for this variant (Variation ID: 379208). Studies have shown that this variant alters RMRP gene expression (PMID: 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 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Mar 26, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The r.147 G>A variant has been reported previously as r.146 G>A in association with cartilage-hair hypoplasia (CHH), a disease with variable expressivity, which can present with defective cellular immunity presenting as a SCID phenotype (Thiel et al., 2007; Ridanpää et al., 2002). In vitro functional studiesdemonstrated that the c.147 G>A variant had the least effect on rRNA cleavage activity, which may explain why it is associated with a milder phenotype (Thiel et al., 2007). We interpret this variant as pathogenic.

Cartilage-Hair Hypoplasia-Anauxetic Dysplasia Spectrum Disorders Pathogenic:1

Jan 29, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RMRP n.147G>A variant, which is also referred to as n.146G>A, is a single nucleotide substitution within the transcribed region that has been reported in a homozygous state in one individual with cartilage-hair hypoplasia (CHH) and in a compound heterozygous state in five unrelated individuals with a diagnosis of or features consistent with CHH (Ridanpää et al. 2002; Bonafé et al. 2005; Kavadas et al. 2008; Türkkani-Asal et al. 2009). The n.147G>A variant is reported at a frequency of 0.000046 in the European (non-Finnish) population of the Genome Aggregation Database. It affects a highly conserved nucleotide and is expected to disrupt the hairpin structure topology. In vitro assays in human fibroblasts have shown that n.147G>A results in a mild reduction of mRNA cleavage activity (~5% less than wildtype) and a slightly larger reduction in rRNA cleavage activity (~20-25% less than wildtype) (Thiel et al. 2007). Based on the collective evidence, the n.147G>A variant is classified as pathogenic for cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.72
PhyloP100		7.0
PromoterAI		-0.081	Neutral

Splicing

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

Other links and lift over

dbSNP: rs753874439; hg19: chr9-35657869;