9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT

Variant names:

• chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT
• rs751921616
• ENST00000363046.2:n.-8_-7insACTCTGTGAAGCTACTCTGTGAAGCT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NR_003051.4(RMRP):​n.-8_-7insACTCTGTGAAGCTACTCTGTGAAGCT variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 533,404 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -9.77
• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT is Pathogenic according to our data. Variant chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1067465.Status of the report is criteria_provided_single_submitter, 1 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.-8_-7insACTCTGTGAAGCTACTCTGTGAAGCT		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.-8_-7insACTCTGTGAAGCTACTCTGTGAAGCT		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000792 AC: 1 AN: 126250 AF XY: 0.0000145

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000562 AC: 3 AN: 533404 Hom.: 0 Cov.: 0 AF XY: 0.00000698 AC XY: 2 AN XY: 286710

African (AFR) AF: 0.00 AC: 0 AN: 15384

American (AMR) AF: 0.0000295 AC: 1 AN: 33846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19606

East Asian (EAS) AF: 0.00 AC: 0 AN: 31716

South Asian (SAS) AF: 0.00 AC: 0 AN: 62038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2386

European-Non Finnish (NFE) AF: 0.00000654 AC: 2 AN: 305706

Other (OTH) AF: 0.00 AC: 0 AN: 29704

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Anauxetic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-9.8

Splicing

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

Other links and lift over

dbSNP: rs751921616; hg19: chr9-35658023;