Variant 9-35657872-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NR_003051.3(RMRP):n.147G>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
NR_003051.3 non_coding_transcript_exon

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.04

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 Likely_pathogenic. Variant got 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 id is 379208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35657872-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RMRP	NR_003051.3 linkuse as main transcript	n.147G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1 linkuse as main transcript	n.146G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000460

AC:

AN:

130490

Hom.:

AF XY:

0.0000281

AC XY:

AN XY:

71222

show subpopulations

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 SAS exome

AF:

0.0000893

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000603

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

548094

Hom.:

Cov.:

AF XY:

0.0000337

AC XY:

AN XY:

296792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000288

Gnomad4 ASJ exome

AF:

0.0000499

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000638

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000379

Gnomad4 OTH exome

AF:

0.0000329

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 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 (rs753874439, gnomAD 0.01%). This variant has been observed in individual(s) with RMRP-related conditions (PMID: 12107819, 16244706, 18804272; Invitae). 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 16, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2015

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; RidanpÃ¤Ã¤ 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

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 29, 2021

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 (RidanpÃ¤Ã¤ et al. 2002; BonafÃ© et al. 2005; Kavadas et al. 2008; TÃ¼rkkani-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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.72

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

Other links and lift over