rs1554651532

Variant names:

• chr9-35658032-C-CACAGAGTAGT
• rs1554651532
• ENST00000363046.2:n.-14_-13insACTACTCTGT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_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 (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -3.42
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• 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.: 34

GnomAD4 exome AF: 0.00000944 AC: 5 AN: 529916 Hom.: 0 Cov.: 0 AF XY: 0.00000351 AC XY: 1 AN XY: 284514

African (AFR) AF: 0.00 AC: 0 AN: 15270

American (AMR) AF: 0.00 AC: 0 AN: 33312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19396

East Asian (EAS) AF: 0.00 AC: 0 AN: 31654

South Asian (SAS) AF: 0.00 AC: 0 AN: 61646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2368

European-Non Finnish (NFE) AF: 0.0000165 AC: 5 AN: 303794

Other (OTH) AF: 0.00 AC: 0 AN: 29514

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

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		-3.4

Splicing

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

Other links and lift over

dbSNP: rs1554651532; hg19: chr9-35658029;