rs551450545

Positions:

Variant summary

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

The NR_003051.3(RMRP):n.243A>G variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000861 in 696,526 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

RMRP
NR_003051.3 non_coding_transcript_exon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.16

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:

Genome browser will be placed here

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 9-35657776-T-C is Pathogenic according to our data. Variant chr9-35657776-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35657776-T-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.14). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMRP	NR_003051.3 linkuse as main transcript	n.243A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMRP	ENST00000363046.1 linkuse as main transcript	n.242A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

128784

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

70378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000288

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000845

AC:

AN:

544314

Hom.:

Cov.:

AF XY:

0.0000952

AC XY:

AN XY:

294072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000625

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.0000661

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2021	Variant summary: RMRP n.243A>G (also known as 242A>G) involves the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 128784 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.0001 vs 0.0072), allowing no conclusion about variant significance. The variant, n.243A>G, has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (e.g. Ridanpaa_2002, Bonafe_2005, Kavadas_2008, Ip_2015, Faitelson_2015, Sathishkumar_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Anauxetic dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 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 (rs551450545, gnomAD 0.03%). This variant has been observed in individual(s) with cartilage hair hypoplasia (PMID: 12107819, 18804272, 25663137, 29744913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 242A>G and 242G. ClinVar contains an entry for this variant (Variation ID: 487451). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.91

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