9-35657836-C-T

Variant names:

• chr9-35657836-C-T
• rs1554651153
• ENST00000363046.2:n.184G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000363046.2(RMRP):​n.184G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 548,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RMRP ENST00000363046.2 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 0.451
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4	n.184G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.2	n.184G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000154 AC: 2 AN: 130220 AF XY: 0.0000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000959

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 3 AN: 548036 Hom.: 0 Cov.: 0 AF XY: 0.00000674 AC XY: 2 AN XY: 296766

African (AFR) AF: 0.00 AC: 0 AN: 15686

American (AMR) AF: 0.0000288 AC: 1 AN: 34704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.0000311 AC: 1 AN: 32104

South Asian (SAS) AF: 0.00 AC: 0 AN: 62680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2444

European-Non Finnish (NFE) AF: 0.00000316 AC: 1 AN: 316790

Other (OTH) AF: 0.00 AC: 0 AN: 30408

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:1 Uncertain:1

Aug 22, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Dec 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RMRP n.183G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 1.5e-05 in 130220 control chromosomes. n.183G>A (also listed as n.182G>A) has been reported in the literature as a de novo occurrence in an individual affected with Cartilage-Hair Hypoplasia (Nakashima_2003). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16832578, 14608646). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.45
PromoterAI		0.19	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1554651153; hg19: chr9-35657833;