rs940080676

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000363046.2(RMRP):n.181dupC 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 0.0000519 in 693,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RMRP
ENST00000363046.2 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: -0.164

Publications

0 publications found

Variant links:

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

RMRP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 9-35657838-C-CG is Pathogenic according to our data. Variant chr9-35657838-C-CG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 465202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4 link	n.181dupC		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 link	n.181dupC		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

145276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000570

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00127

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000502

GnomAD2 exomes

AF:

0.0000230

AC:

AN:

130180

AF XY:

0.0000141

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000822

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:

0.000250

GnomAD4 exome

AF:

0.0000255

AC:

AN:

548036

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

296766

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15688

American (AMR)

AF:

0.000259

AC:

AN:

34704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20026

East Asian (EAS)

AF:

0.00

AC:

AN:

32104

South Asian (SAS)

AF:

0.00

AC:

AN:

62680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2444

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

316792

Other (OTH)

AF:

0.000164

AC:

AN:

30406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

145368

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

AN XY:

71172

show subpopulations

African (AFR)

AF:

0.0000568

AC:

AN:

35186

American (AMR)

AF:

0.00127

AC:

AN:

14932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.000497

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000257

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type

Pathogenic:1Uncertain:1

Feb 25, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 02, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RMRP n.180dupC (also known as NC_000009.11: chr9:g.35657836dupG or 179_180insC in the literature) alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 2.3e-05 in 130180 control chromosomes (gnomAD). n.180dupC has been observed in individual(s) affected with Cartilage-Hair Hypoplasia where it was seen in trans with a pathogenic variant (Hermanns_2006, internal testing). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 16838329). ClinVar contains an entry for this variant (Variation ID: 465202). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Anauxetic dysplasia

Pathogenic:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

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 present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of cartilage-hair hypoplasia anauxetic dysplasia spectrum disorder (PMID: 16838329; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 179_180insC. ClinVar contains an entry for this variant (Variation ID: 465202). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.16

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over