Variant rs727502778 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The 9-35658020-C-CGTCCTCAGCTTCACAGA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 688,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

RMRP
NR_003051.3 upstream_gene

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -12.3

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-35658020-C-CGTCCTCAGCTTCACAGA is Pathogenic according to our data. Variant chr9-35658020-C-CGTCCTCAGCTTCACAGA is described in ClinVar as [Pathogenic]. Clinvar id is 14214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMRP	NR_003051.3 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMRP	ENST00000363046.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000314

AC:

AN:

127388

Hom.:

AF XY:

0.0000287

AC XY:

AN XY:

69588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000420

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000965

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000416

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

536904

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

289060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000584

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000315

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000844

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2018	Variant summary: RMRP n.-19_-3dup17 (also known as r.-19_-3dup17) variant involves the duplication of 17 nucleotides in the promoter region of RMRP, which is located between the TATA box (-33 to -25) and the transcription initiation site. The variant allele was found at a frequency of 3.3e-05 in 153424 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (3.3e-05 vs 0.0072), allowing no conclusion about variant significance. n.-19_-3dup17 has been reported in the literature in at least two individuals affected with Cartilage-Hair Hypoplasia in compound heterozygous state (Ridanpaa_2001, Bonafa_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, variant n.-20_-19insTCTGTGAAGCTGGGGAC (rs727502779) that resembles to our variant of interest with one nucleotide difference (the 13th nt) has been reported in CHH patient and the expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene (Nakashima_RMRP_AJMG_2003). One reputable database, OMIM, submitted clinical-significance assessments for this variant to ClinVar and classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 26, 2001	- -

Anauxetic dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 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 (rs727502778, gnomAD 0.009%). This variant has been observed in individuals with cartilage-hair hypoplasia (PMID: 11207361). Other insertions and duplications immediately upstream of the coding sequence have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16244706, 11207361, 12107819). This variant is also known as dupTCTGTGAAGCTGAGGAC at -3. ClinVar contains an entry for this variant (Variation ID: 14214). While functional studies for this variant have not been reported, experimental analyses using patient derived cells, as well as in vitro transfection studies, have shown that promoter insertions result in silencing of RMRP transcription and reduced expression of the gene product (PMID: 11207361, 16254002). 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

Apr 19, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2023

Published functional studies demonstrate that this variant leads to a loss of RMRP expression (Nakashima et al., 2003); Duplication variants in the promoter region disrupt RNA folding/structure; Also known as r.-20_-4dup17; This variant is associated with the following publications: (PMID: 33726816, 11207361, 14608646) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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