9-35657761-T-C

Variant names:

• chr9-35657761-T-C
• rs1177828515
• ENST00000363046.2:n.259A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NR_003051.4(RMRP):​n.259A>G 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 0.00000187 in 535,868 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: 34)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: RMRP NR_003051.4 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.809
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4	n.259A>G		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.259A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000187 AC: 1 AN: 535868 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 288262

African (AFR) AF: 0.00 AC: 0 AN: 15502

American (AMR) AF: 0.00 AC: 0 AN: 34208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19668

East Asian (EAS) AF: 0.00 AC: 0 AN: 31822

South Asian (SAS) AF: 0.00 AC: 0 AN: 62274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2406

European-Non Finnish (NFE) AF: 0.00000325 AC: 1 AN: 307254

Other (OTH) AF: 0.00 AC: 0 AN: 29762

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000905 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anauxetic dysplasia Uncertain:1

Apr 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RMRP-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.80
PhyloP100		0.81

Splicing

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

Other links and lift over

dbSNP: rs1177828515; hg19: chr9-35657758;