rs144972972

Positions:

chr6-151430154-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_017909.4(RMND1):c.713A>G(p.Asn238Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,602,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

RMND1
NM_017909.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:1

Conservation

PhyloP100: 5.59

Variant links:

Genes affected

RMND1 (HGNC:21176): (required for meiotic nuclear division 1 homolog) The protein encoded by this gene belongs to the evolutionary conserved sif2 family of proteins that share the DUF155 domain in common. This protein is thought to be localized in the mitochondria and involved in mitochondrial translation. Mutations in this gene are associated with combined oxidative phosphorylation deficiency-11. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

RMND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-151430154-T-C is Pathogenic according to our data. Variant chr6-151430154-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225255.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=9}. Variant chr6-151430154-T-C is described in Lovd as [Pathogenic]. Variant chr6-151430154-T-C is described in Lovd as [Likely_pathogenic]. Variant chr6-151430154-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RMND1	NM_017909.4 linkuse as main transcript	c.713A>G	p.Asn238Ser	missense_variant	5/12	ENST00000444024.3	NP_060379.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMND1	ENST00000444024.3 linkuse as main transcript	c.713A>G	p.Asn238Ser	missense_variant	5/12	3	NM_017909.4	ENSP00000412708	P1	Q9NWS8-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000201

AC:

AN:

249272

Hom.:

AF XY:

0.000230

AC XY:

AN XY:

134872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000880

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000370

AC:

537

AN:

1450126

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

271

AN XY:

721914

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.0000905

Gnomad4 ASJ exome

AF:

0.000655

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000586

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000433

Gnomad4 OTH exome

AF:

0.000417

GnomAD4 genome

AF:

0.000237

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000460

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 11

Pathogenic:5Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2022	Variant summary: RMND1 c.713A>G (p.Asn238Ser) results in a conservative amino acid change located in the Domain of unknown function DUF155 (IPR003734) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 249272 control chromosomes. This frequency does not allow conclusions about variant significance. c.713A>G has been reported in the literature in multiple individuals affected with features of Combined Oxidative Phosphorylation Defect Type 11 ranging from muscle defects, seizures, deafness, and renal tubular acidosis (example, Broenen_2019, Janer_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Molecular and Human Genetics, Baylor College of Medicine	Apr 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 238 of the RMND1 protein (p.Asn238Ser). This variant is present in population databases (rs144972972, gnomAD 0.03%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency 11 (PMID: 25604853, 26395190, 31506229, 31568715). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225255). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RMND1 protein function. Experimental studies have shown that this missense change affects RMND1 function (PMID: 25604853). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27412952, 27159321, 28939701, 27350610, 26395190, 25473036, 25058219, 25604853, 27843092, 28844315, 29071585, 29671881, 31506229, 31568715, 32746448) -

Mitochondrial oxidative phosphorylation disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2018

The p.Asn238Ser variant in RMND1 has been reported in the homozygous or compound heterozygous state in at least 10 individuals with combined oxidative phosphory lation deficiency (Taylor 2014, Janer 2015, Vanderver 2016, Ng 2016, Gupta 2016, Ulrick 2017). In vitro functional studies provide some evidence that the p.Asn2 38Ser variant may impact protein function (Janer 2015); however, these types of assays may not accurately represent biological function. This variant has been i dentified in 0.03% (44/126078) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144972972). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with a recessive carrier frequency. In summary, this varian t meets criteria to be classified as pathogenic for combined oxidative phosphory lation deficiency in an autosomal recessive manner based upon presence in affect ed individuals, frequency in controls, and functional evidence. ACMG/AMP Criteri a applied: PM3_VeryStrong; PM2_Supporting; PS3_Supporting -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.713A>G (p.N238S) alteration is located in exon 5 (coding exon 4) of the RMND1 gene. This alteration results from an A to G substitution at nucleotide position 713, causing the asparagine (N) at amino acid position 238 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.02% (54/280666) total alleles studied. The highest observed frequency was 0.04% (47/128420) of European (non-Finnish) alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in RMND1 in multiple individuals with RMND1-related combined oxidative phosphorylation deficiency (Taylor, 2014; Janer, 2015; Ng, 2016; Gupta, 2016; Vanderver, 2016; Ravn, 2016; van Dieman, 2017; Ulrick, 2017; Demain, 2018; Shayoto, 2019; Broenen, 2019). Experimental studies show that this alteration leads to reduced RMND1 activity in patient-derived cells (Janer, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Mitochondrial disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Dec 22, 2015

- -

Nephronophthisis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Aug 10, 2014

This patient is heterozygous for a known pathogenic variant, c.713A>G (p.Asn238Ser), in the RMND1 gene. This variant has been previously reported in conjunction with a second pathogenic variant in a patient with epileptic encephalopathy and lactic acidosis. Functional studies have shown that this variant causes a decrease in the level of RMND1 protein (Janer et al 2015: European Journal of Human Genetics, 1-7). This variant is therefore considered to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Uncertain

-0.030

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.5

.;D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

0.99

D;D;.

Vest4

0.94, 0.94

MVP

0.69

MPC

0.71

ClinPred

0.67

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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