rs1554651524

Variant names:

• chr9-35658031-T-TCACAGAGTAG
• rs1554651524
• ENST00000363046.2:n.-13_-12insCTACTCTGTG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NR_003051.4(RMRP):​n.-13_-12insCTACTCTGTG variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 530,404 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: "SCV005394714: At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in reduced promoter activity compared to the WT RMRP promoter in vitro (Hermanns_2005)." 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: 0.0000019 (0 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -3.94
• Publications: 0 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: G2P, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

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

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005394714: At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in reduced promoter activity compared to the WT RMRP promoter in vitro (Hermanns_2005).; SCV002218286: Studies have shown that this variant alters RMRP gene expression (PMID: 16254002).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35658031-T-TCACAGAGTAG is Pathogenic according to our data. Variant chr9-35658031-T-TCACAGAGTAG is described in ClinVar as Pathogenic. ClinVar VariationId is 557391.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.-13_-12insCTACTCTGTG		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.-13_-12insCTACTCTGTG		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000189 AC: 1 AN: 530404 Hom.: 0 Cov.: 0 AF XY: 0.00000351 AC XY: 1 AN XY: 284796

African (AFR) AF: 0.00 AC: 0 AN: 15290

American (AMR) AF: 0.00 AC: 0 AN: 33378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 31666

South Asian (SAS) AF: 0.00 AC: 0 AN: 61724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2372

European-Non Finnish (NFE) AF: 0.00000329 AC: 1 AN: 304086

Other (OTH) AF: 0.00 AC: 0 AN: 29538

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Metaphyseal chondrodysplasia, McKusick type (2)
1	-	-	Anauxetic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.9

Splicing

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

Other links and lift over

dbSNP: rs1554651524; hg19: chr9-35658028;