chr9-35657776-T-C

Variant names:

• chr9-35657776-T-C
• rs551450545
• ENST00000363046.1:n.242A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NR_003051.4(RMRP):​n.244A>G variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000861 in 696,526 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: 𝑓 0.000092 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: RMRP NR_003051.4 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35657776-T-C is Pathogenic according to our data. Variant chr9-35657776-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 487451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35657776-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14). . 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>G		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1	n.242A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152212 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 15 AN: 128784 Hom.: 0 AF XY: 0.000128 AC XY: 9 AN XY: 70378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000288

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000845 AC: 46 AN: 544314 Hom.: 0 Cov.: 0 AF XY: 0.0000952 AC XY: 28 AN XY: 294072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000625

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.0000661

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152212 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74366

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:2

Jun 16, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RMRP n.243A>G (also known as 242A>G) involves the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 128784 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.0001 vs 0.0072), allowing no conclusion about variant significance. The variant, n.243A>G, has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (e.g. Ridanpaa_2002, Bonafe_2005, Kavadas_2008, Ip_2015, Faitelson_2015, Sathishkumar_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Anauxetic dysplasia Pathogenic:1

Dec 24, 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 (rs551450545, gnomAD 0.03%). This variant has been observed in individual(s) with cartilage hair hypoplasia (PMID: 12107819, 18804272, 25663137, 29744913). 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 242A>G and 242G. ClinVar contains an entry for this variant (Variation ID: 487451). 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

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RMRP-related disorder Pathogenic:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RMRP n.243A>G is a noncoding alteration. This variant has been documented in the compound heterozygous state in multiple unrelated individuals affected with cartilage hair hypoplasia (described as 242G or g.242A>G in Ridanpaa et al. 2002. PubMed ID: 12107819; Kavadas et al. 2008. PubMed ID: 18804272; Ip et al. 2015. PubMed ID: 25663137; Sathishkumar et al. 2018. PubMed ID: 29744913). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD. Based on the available evidence, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs551450545; hg19: chr9-35657773;