Genetic Variant RMRP:n.250C>T (chr9-35657770-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NR_003051.4(RMRP):n.250C>T variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 543,104 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

RMRP
NR_003051.4 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 8.94

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.09).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4 link	n.250C>T		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.250C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

543104

Hom.:

Cov.:

AF XY:

0.00000341

AC XY:

AN XY:

293258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15662

American (AMR)

AF:

0.00

AC:

AN:

34592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19904

East Asian (EAS)

AF:

0.00

AC:

AN:

31986

South Asian (SAS)

AF:

0.00

AC:

AN:

62538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2424

European-Non Finnish (NFE)

AF:

0.00000320

AC:

AN:

312744

Other (OTH)

AF:

0.00

AC:

AN:

30184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 23, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RMRP n.249C>T (also known as NC_000009.11: chr9:g.35657767G>A) alters a nucleotide in the non-coding RNA. The variant was absent in 128060 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. n.249C>T has been observed in the compound heterozygous state in at least one individual affected with Cartilage-Hair Hypoplasia (Bonaf_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Cartilage-Hair Hypoplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is also known as n.248CT and n.250C>T. The following publication have been ascertained in the context of this evaluation (PMID: 16244706). ClinVar contains an entry for this variant (Variation ID: 552824). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Metaphyseal chondrodysplasia, McKusick type

Uncertain:1

Jul 20, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

8.9

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over