rs1383432106

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.258_267delCAGCGCGGCT variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000717 in 683,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

RMRP
ENST00000363046.2 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 7.11

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 9-35657752-CAGCCGCGCTG-C is Pathogenic according to our data. Variant chr9-35657752-CAGCCGCGCTG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 465208.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4 link	n.258_267delCAGCGCGGCT		non_coding_transcript_exon_variant	Exon 1 of 1	ENST00000363046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.2 link	n.258_267delCAGCGCGGCT		non_coding_transcript_exon_variant	Exon 1 of 1	6	NR_003051.4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

GnomAD2 exomes

AF:

0.000318

AC:

AN:

122650

AF XY:

0.000254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00126

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:

0.00234

GnomAD4 exome

AF:

0.0000809

AC:

AN:

531544

Hom.:

AF XY:

0.0000770

AC XY:

AN XY:

285720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15460

American (AMR)

AF:

0.00109

AC:

AN:

34006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19288

East Asian (EAS)

AF:

0.00

AC:

AN:

31792

South Asian (SAS)

AF:

0.00

AC:

AN:

61506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2384

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

304726

Other (OTH)

AF:

0.000203

AC:

AN:

29594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.0000394

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.000393

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000982

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type

Pathogenic:1Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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.35657755_35657764del variant is a 10 base pair deletion in RMRP (a non-coding gene). On transcript NR_003051.4 this variant is known as n.256_265delCTCAGCGCGG or n.258_267delCAGCGCGGCT (depending on left vs right shuffling). On transcript NR_003051.3 the variant is known as n.255_264delCTCAGCGCGG or n.257_266delCAGCGCGGCT (depending on left vs right shuffling). The variant may also be referred to as g.254_263delCTCAGCGCGG in the literature. The overall minor allele frequency (MAF) of this variant in gnomAD v4.1.0 is 0.00007166 (49/683800 alleles) and the highest subpopulation MAF (in Admixed American subpopulation) is 0.0008724 (43/49292 alleles). This exceeds the SCID VCEP's criteria for PM2 (<0.0000447) but does not exceed the criteria for BS1 (> 0.00089), therefore no population criteria code is met. Of note, although PM2 is not met, the highest population frequency in gnomAD is the Admixed American subpopulation and all affected individuals identified in the literature are likely from this same subpopulation. This variant has been identified in the literature in 3 unrelated female probands, all of Hispanic or Spanish/Mexican descent, affected with cartilage hair hypoplasia or anauxetic dysplasia (PMID: 17701897, 16838329). All 3 probands have metaphyseal dysplasia (1.0 point) meeting PP4 criteria. In addition to metaphyseal dysplasia, proband P9 in PMID: 16838329 also has hypotrichosis (0.5 point) (1.5 points total, meeting PP4 criteria) and proband P20 also has hypotrichosis (0.5 point), Hirschsprung disease (0.25 point), and T cell lymphopenia (0.5 point) (2.25 points total, meeting PP4_Moderate criteria). All 3 probands have a co-occurring second variant in RMRP. For proband P9 (PMID: 16838329), the co-occurring variant is 116A>G (NR_003051.3:n.117A>G) which has not yet been classified by the SCID VCEP and phase is unknown (0 point for PM3). For proband P20 (PMID: 16838329), the co-occurring variant is 195C>T (NR_003051.3:n.196C>T) which is classified as Pathogenic by the SCID VCEP, however, phase is unknown (0.5 point for PM3). For the proband in PMID: 17701897, the co-occurring variant is 195C>T (NR_003051.3:n.196C>T) which is classified as Pathogenic by the SCID VCEP, and the variants were confirmed in trans via parental testing (1 point for PM3). In addition to these 3 probands identified in the literature, this variant has also been observed in a male proband (of Hispanic descent) with a co-occurring RMRP variant in trans (SCV000640115.6) and indication of disproportionate short stature. The co-occurring variant is n.196C>T which is classified Pathogenic by the SCID VCEP and the variants are confirmed in trans (1 point for PM3). PMID: 17701897 additionally reports that sequencing of the RMRP RT-PCR product of patient with this variant showed absence of detectable levels of the mutation allele. The authors assert this variant is likely a null allele and therefore did not do further analysis for this variant in functional assays. This data does not qualify for PS3 under the SCID VCEP specifications for RMRP. In summary, this variant is classified as Likely Pathogenic based on the following ACMG codes PP4_Moderate (2.25 points), PM3_strong (2.5 points) (SCID VCEP RMRP specifications pilot v1). -

Anauxetic dysplasia 1

Pathogenic:1

Sep 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Anauxetic dysplasia

Pathogenic:1

Nov 17, 2024

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 0.08%). This variant has been observed in individual(s) with cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders (PMID: 16838329, 17701897). 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 256_265delCAGCGCGGCT and g.254_263delCTCAGCGCGG. ClinVar contains an entry for this variant (Variation ID: 465208). Studies have shown that this variant alters RMRP gene expression (PMID: 17701897). For these reasons, this variant has been classified as Pathogenic. -

Metaphyseal chondrodysplasia, McKusick type;C1834821:Metaphyseal dysplasia without hypotrichosis;C4551965:Anauxetic dysplasia 1

Pathogenic:1

Apr 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RMRP-related disorder

Pathogenic:1

Nov 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is also referred to as 256_265del and g.254_263del in the literature. It has been reported with a second RMRP variant in individuals with cartilage hair hypoplasia and anauxetic dysplasia (Hermanns et al. 2006. PubMed ID: 16838329; Thiel et al. 2007. PubMed ID: 17701897). RT-PCR studies showed no detectable levels of the RMRP product (Thiel et al. 2007. PubMed ID: 17701897). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.1

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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