Variant 9-35658030-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NR_003051.4(RMRP):n.-11A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 682,932 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

RMRP
NR_003051.4 upstream_gene

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -4.18

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 9-35658030-T-G is Benign according to our data. Variant chr9-35658030-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550921.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4 link	n.-11A>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1 link	n.-13A>C		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

220

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000578

AC:

AN:

124488

Hom.:

AF XY:

0.000528

AC XY:

AN XY:

68130

show subpopulations

Gnomad AFR exome

AF:

0.00497

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000971

Gnomad SAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000787

GnomAD4 exome

AF:

0.000305

AC:

162

AN:

530596

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

284938

show subpopulations

Gnomad4 AFR exome

AF:

0.00366

Gnomad4 AMR exome

AF:

0.000990

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000316

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.0000303

Gnomad4 NFE exome

AF:

0.0000986

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.00146

AC:

223

AN:

152336

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00474

Gnomad4 AMR

AF:

0.000718

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.00176

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 13, 2019

Variant summary: The RMRP variant, n.-12A>C is located in the promoter region and is also referred to as n.-13A>C. Duplications in this region have been classified as pathogenic, although single nucleotide changes have not commonly been classified in this region to be pathogenic. The variant allele was found at a frequency of 0.00067 in 150636 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.00067 vs 0.0072), allowing no conclusion about variant significance. n.-12A>C has been reported in the literature in an individual affected with Cartilage-Hair Hypoplasia, which authors indicate the cause for disease was g.97G>A and g.27G>C. Therefore, this variant was in cis with g.27G>C and assumed to be nonpathogenic by the authors (Cherkaoui Jaouad_2015). 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 likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2019

- -

Metaphyseal chondrodysplasia, McKusick type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Mar 22, 2017

- -

Anauxetic dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2025

- -

RMRP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0090

DANN

Benign

0.44

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over