rs772443941

chr9-35658014-G-Achr9-35658014-G-Cchr9-35658014-G-T

Variant summary

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

The NR_003051.3(RMRP):n.5C>T 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 0.0000911 in 691,230 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: 0.000091 (0 hom.)
• Consequence: RMRP NR_003051.3 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.79

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 9-35658014-G-A is Pathogenic according to our data. Variant chr9-35658014-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35658014-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMRP	NR_003051.3	n.5C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMRP	ENST00000363046.1	n.4C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152090 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000966

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 14 AN: 128262 Hom.: 0 AF XY: 0.000100 AC XY: 7 AN XY: 70028

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000193

Gnomad SAS exome AF: 0.000405

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000413

Gnomad OTH exome AF: 0.000254

GnomAD4 exome AF: 0.0000909 AC: 49 AN: 539140 Hom.: 0 Cov.: 0 AF XY: 0.0000929 AC XY: 27 AN XY: 290530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000629

Gnomad4 SAS exome AF: 0.000321

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152090 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74312

Gnomad4 AFR AF: 0.0000966

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). As this gene encodes a noncoding RNA, there is no corresponding protein annotation. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 16244706, 16838329, 17015150, 18804272, 20375313, 29744913). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000552477). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2018	Variant summary: The RMRP n.5C>T (also known as n.4C>T) variant was found at a frequency of 0.00012 in 154346 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.00012 vs 0.0072), allowing no conclusion about variant significance. The variant, n.5C>T, has been reported in the literature in multiple individuals affected with Cartilage-Hair Hypoplasia (Bordon_2010, Hermanns_2006, Kavadas_2008, Munoz-Robles_2006, Bonafe_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 12, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2020	Published functional studies demonstrate a damaging effect on rRNA and mRNA cleavage activities (Thiel et al., 2007); This variant is associated with the following publications: (PMID: 16244706, 16838329, 17015150, 18804272, 19626344, 25663137, 29744913, 12107819, 17701897, 20375313) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	RMRP: PM3:Strong, PM2, PS3:Moderate, PS4:Moderate -

Anauxetic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

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 (rs772443941, gnomAD 0.04%). This variant has been observed in individual(s) with autosomal recessive cartilage-hair hypoplasia (PMID: 16244706, 16838329, 17015150, 19626344, 20375313, 25663137, 29744913). This variant is also known as 4C>T. ClinVar contains an entry for this variant (Variation ID: 552477). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs772443941; hg19: chr9-35658011;