Genetic Variant RMRP:n.246_254delGGGGCTCAT (chr9-35657765-AATGAGCCCC-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NR_003051.4(RMRP):n.246_254delGGGGCTCAT variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 540,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

RMRP
NR_003051.4 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4 link	n.246_254delGGGGCTCAT		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.246_254delGGGGCTCAT		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000785

AC:

AN:

127462

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000185

AC:

AN:

540272

Hom.:

AF XY:

0.00

AC XY:

AN XY:

291274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15610

American (AMR)

AF:

0.00

AC:

AN:

34508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19802

East Asian (EAS)

AF:

0.00

AC:

AN:

31918

South Asian (SAS)

AF:

0.00

AC:

AN:

62446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2414

European-Non Finnish (NFE)

AF:

0.00000322

AC:

AN:

310514

Other (OTH)

AF:

0.00

AC:

AN:

30026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Anauxetic dysplasia

Uncertain:1

May 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with RMRP-related conditions. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this non-coding change is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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