Genetic Variant RMRP:n.-21C>G (chr9-35658038-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NR_003051.4(RMRP):n.-19C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 671,728 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 7 hom., cov: 34)

Exomes 𝑓: 0.0027 ( 5 hom. )

Consequence

RMRP
NR_003051.4 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.23

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 9-35658038-G-C is Benign according to our data. Variant chr9-35658038-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 533769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RMRP	NR_003051.4 link	n.-19C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1 link	n.-21C>G		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00478

AC:

728

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00984

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00221

AC:

262

AN:

118506

Hom.:

AF XY:

0.00199

AC XY:

129

AN XY:

64822

show subpopulations

Gnomad AFR exome

AF:

0.0104

Gnomad AMR exome

AF:

0.00144

Gnomad ASJ exome

AF:

0.000432

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000245

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.00219

GnomAD4 exome

AF:

0.00267

AC:

1387

AN:

519422

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

672

AN XY:

277790

show subpopulations

Gnomad4 AFR exome

AF:

0.0123

Gnomad4 AMR exome

AF:

0.00138

Gnomad4 ASJ exome

AF:

0.000264

Gnomad4 EAS exome

AF:

0.0000318

Gnomad4 SAS exome

AF:

0.000165

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.00218

Gnomad4 OTH exome

AF:

0.00334

GnomAD4 genome

AF:

0.00490

AC:

746

AN:

152306

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

400

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0103

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.00229

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00441

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RMRP: BS1, BS2 -

not specified

Benign:1

Jul 13, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RMRP n.-20C>G is located in the untranscribed region upstream of the RMRP gene region. This variant is also known as -21C>G. The variant allele was found at a frequency of 0.003 in 149896 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia phenotype (0.0072), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of n.-20C>G in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Metaphyseal chondrodysplasia, McKusick type

Benign:1

Apr 14, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Anauxetic dysplasia

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RMRP-related disorder

Benign:1

Sep 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

-0.76

CADD

Benign

0.026

DANN

Benign

0.47

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