Variant 9-35657891-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NR_003051.4(RMRP):n.129G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 700,432 control chromosomes in the GnomAD database, including 2 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 0.0032 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0025 ( 1 hom. )

Consequence

RMRP
NR_003051.4 non_coding_transcript_exon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.70

Variant links:

Genes affected

RMRP (HGNC:):

RMRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 9-35657891-C-G is Benign according to our data. Variant chr9-35657891-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465201.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr9-35657891-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RMRP	NR_003051.4 linkuse as main transcript	n.129G>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1 linkuse as main transcript	n.127G>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

489

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00538

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00255

AC:

333

AN:

130502

Hom.:

AF XY:

0.00247

AC XY:

176

AN XY:

71226

show subpopulations

Gnomad AFR exome

AF:

0.00427

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00839

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000893

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00324

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.00249

AC:

1367

AN:

548096

Hom.:

Cov.:

AF XY:

0.00237

AC XY:

703

AN XY:

296794

show subpopulations

Gnomad4 AFR exome

AF:

0.00528

Gnomad4 AMR exome

AF:

0.00294

Gnomad4 ASJ exome

AF:

0.00699

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000160

Gnomad4 FIN exome

AF:

0.000362

Gnomad4 NFE exome

AF:

0.00281

Gnomad4 OTH exome

AF:

0.00352

GnomAD4 genome

AF:

0.00321

AC:

489

AN:

152336

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

203

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00536

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00275

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00252

Hom.:

Bravo

AF:

0.00353

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type;C1834821:Metaphyseal dysplasia without hypotrichosis;C4551965:Anauxetic dysplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jun 14, 2021

RMRP NR_003051.3 exon 1 n.128G>C: This variant has not been reported in the literature but is present in 0.5% (223/41466) of African alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-35657891-C-G?dataset=gnomad_r3).This variant is present in ClinVar (Variation ID:465201). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

RMRP-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2023

The RMRP n.128G>C is a noncoding alteration. This variant was reported in the homozygous state in at least one individual with primary immunodeficiency, who also carried a homozygous n.*2T>C variant in the RMRP gene (Yu et al. 2016. PubMed ID: 27484032; reported as g.35657888 in Table S2, Platt et al 2020. PubMed ID: 32888943) and found in one individual undergoing carrier testing (Abulí et al. 2016. PubMed ID: 26990548). This variant is reported in 0.81% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-35657888-C-G). In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/465201/). Although we suspect this variant could be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 28, 2022

Variant summary: RMRP n.128G>C alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.0026 in 130502 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.0026 vs 0.0072), allowing no conclusion about variant significance. n.128G>C has been reported in the literature in two homozygous individuals affected with primary immunodeficiency (Yu_2016, Platt_2021) but it has also been reported as homozygous occurrence in one control individual in gnomAD v3.1.2. Furthermore, the variant has been observed in another control individual in proven compound heterozygosity with a known pathogenic variant (n.71A>G) (Bonafe_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign for Cartilage-Hair Hypoplasia. -

Metaphyseal chondrodysplasia, McKusick type

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 08, 2020

- -

Anauxetic dysplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

RMRP: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.46

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