ENST00000363046.2:n.182G>A

Variant names:

• chr9-35657838-C-T
• rs1004469515
• ENST00000363046.2:n.182G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The ENST00000363046.2(RMRP):​n.182G>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 0.0000231 in 693,312 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001362268: The most pronounced variant effect results in 10%-<30% of normal RMRP expression (Hermanns 2005).". The gene RMRP is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RMRP ENST00000363046.2 non_coding_transcript_exon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.0390
• 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

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001362268: The most pronounced variant effect results in 10%-<30% of normal RMRP expression (Hermanns 2005).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35657838-C-T is Pathogenic according to our data. Variant chr9-35657838-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 928881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48). . 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.182G>A		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.182G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000275 AC: 4 AN: 145276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000461 AC: 6 AN: 130180 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000247

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: 0.0000219 AC: 12 AN: 548036 Hom.: 0 Cov.: 0 AF XY: 0.0000135 AC XY: 4 AN XY: 296766

African (AFR) AF: 0.00 AC: 0 AN: 15688

American (AMR) AF: 0.000144 AC: 5 AN: 34704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 32104

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33192

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

European-Non Finnish (NFE) AF: 0.00000947 AC: 3 AN: 316792

Other (OTH) AF: 0.0000987 AC: 3 AN: 30406

GnomAD4 genome AF: 0.0000275 AC: 4 AN: 145276 Hom.: 0 Cov.: 33 AF XY: 0.0000422 AC XY: 3 AN XY: 71062

African (AFR) AF: 0.00 AC: 0 AN: 35090

American (AMR) AF: 0.000134 AC: 2 AN: 14912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 1992

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Anauxetic dysplasia (1)
1	-	-	Metaphyseal chondrodysplasia, McKusick type (1)
1	-	-	Metaphyseal chondrodysplasia, McKusick type;C1834821:Metaphyseal dysplasia without hypotrichosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.2
DANN	Benign	0.96
PhyloP100		-0.039
PromoterAI		0.10	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1004469515; hg19: chr9-35657835;