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 (★★★). The gene RMRP is included in the ClinGen Criteria Specification Registry.

• 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:3 U:1
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Specifications for RMRP are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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 ClinVar as Likely_pathogenic. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000363046.2. 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.244A>C		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.244A>C		non_coding_transcript_exon	Exon 1 of 1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Metaphyseal chondrodysplasia, McKusick type (3)
1	-	-	Anauxetic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs551450545;

hg19: chr9-35657773;