ENST00000363046.2:n.244A>C

Variant names:

• chr9-35657776-T-G
• rs551450545
• ENST00000363046.2:n.244A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000363046.2(RMRP):​n.244A>C variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000184 in 544,314 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 Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: RMRP ENST00000363046.2 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 7.16
• Publications: 1 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35657776-T-G is Pathogenic according to our data. Variant chr9-35657776-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 553173.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.12). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4	n.244A>C		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.244A>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000184 AC: 1 AN: 544314 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 294072

African (AFR) AF: 0.00 AC: 0 AN: 15672

American (AMR) AF: 0.00 AC: 0 AN: 34618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19962

East Asian (EAS) AF: 0.00 AC: 0 AN: 32008

South Asian (SAS) AF: 0.00 AC: 0 AN: 62618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2428

European-Non Finnish (NFE) AF: 0.00000319 AC: 1 AN: 313640

Other (OTH) AF: 0.00 AC: 0 AN: 30258

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:1 Uncertain:1

Aug 01, 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. -

Jun 10, 2025

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NC_000009.12:g.35657776T>G is present in a frequency of 0.000006567 Grpmax filtering AF with only 1 allele in 152268, which is below the PM2_Supporting threshold that the SCID VCEP has established, therefore meeting this criterion. Internal data: at least one patient has presented with metaphyseal dysplasia (disproportionate short stature + radiographic evidence) (+1.0), skeletal dysplasia gene panel or WES/WGS conducted with no alternative genetic diagnosis (+1.0) and hypotrichosis (+0.5) reaching a total of 2.5 points. Therefore PP4_Moderate is met. Internal data: this variant has been confirmed in trans with NR_003051.3:n.196C>T (classified Pathogenic by VCEP +1.0) in a proband with the short disproportionate stature, rhizomelic dysplasia, and sparse light hair. Therefore PM3 is met. Finally, this variant (n.244A>C) is located at position 244, which is the same nucleotide that another variant has been classified as Likely Pathogenic in position 244 (n.244A>G), meeting PS1_Supporting. In summary, this variant is classified as Likely Pathogenic for Autosomal Recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PS1_Supporting, PM3, PP4_Moderate (SCID VCEP RMRP specifications version 1). -

Anauxetic dysplasia Pathogenic:1

Apr 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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 been observed in individual(s) with clinical features of cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553173). This variant disrupts the n.243A nucleotide in the RMRP gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12107819, 18804272, 25663137, 29744913). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. -

not specified Uncertain:1

Mar 15, 2024

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.243A>C alters a conserved nucleotide in the non-coding RNA. The variant was absent in 128784 control chromosomes (gnomAD). To our knowledge, no occurrence of n.243A>C in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 553173). Additionally, a variant disrupting the same nucleotide, n.243A>G, has been classified as pathogenic by our lab. 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	-0.12
CADD	Benign	21
DANN	Benign	0.92
PhyloP100		7.2

Splicing

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

Other links and lift over

dbSNP: rs551450545; hg19: chr9-35657773;