9-35658038-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The 9-35658038-G-C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (5 hom.)
• Consequence: RMRP NR_003051.3 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.23

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 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 [Benign]. Clinvar id is 533769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RMRP	NR_003051.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMRP	ENST00000363046.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 728 AN: 152188 Hom.: 3 Cov.: 34

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.: 1 AF XY: 0.00199 AC XY: 129 AN XY: 64822

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.: 5 Cov.: 0 AF XY: 0.00242 AC XY: 672 AN XY: 277790

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.: 7 Cov.: 34 AF XY: 0.00537 AC XY: 400 AN XY: 74488

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.: 1

Bravo AF: 0.00441

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 13, 2022

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 14, 2020

- -

Anauxetic dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

RMRP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

RMRP: BS1, BS2 -

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

Other links and lift over

dbSNP: rs183974004; hg19: chr9-35658035;