Genetic Variant RMRP:n.-14_-13insACTACTCTGT (chr9-35658032-C-CACAGAGTAGT) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3PM2PP5_Very_Strong

The NR_003051.4(RMRP):n.-14_-13insACTACTCTGT variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000944 in 529,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004814083: "functional studies have shown that this type of alteration result in reduced expression of the RMRP gene". PMID:11207361, PMID:16254002" and additional evidence is available in ClinVar. The gene RMRP is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

RMRP
NR_003051.4 upstream_gene

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -3.42

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

cartilage-hair hypoplasia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

RMRP links:

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ACMG classification

Specifications for RMRP are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004814083: "functional studies have shown that this type of alteration result in reduced expression of the RMRP gene". PMID:11207361, PMID:16254002; SCV002199177: 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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-35658032-C-CACAGAGTAGT is Pathogenic according to our data. Variant chr9-35658032-C-CACAGAGTAGT is described in ClinVar as Pathogenic. ClinVar VariationId is 550938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_003051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.-14_-13insACTACTCTGT		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.-14_-13insACTACTCTGT		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000944

AC:

AN:

529916

Hom.:

Cov.:

AF XY:

0.00000351

AC XY:

AN XY:

284514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15270

American (AMR)

AF:

0.00

AC:

AN:

33312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19396

East Asian (EAS)

AF:

0.00

AC:

AN:

31654

South Asian (SAS)

AF:

0.00

AC:

AN:

61646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2368

European-Non Finnish (NFE)

AF:

0.0000165

AC:

AN:

303794

Other (OTH)

AF:

0.00

AC:

AN:

29514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Metaphyseal chondrodysplasia, McKusick type (2)

Anauxetic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.4

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over