rs144972972

chr6-151430154-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:1
• Conservation: PhyloP100: 5.59

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]

ACMG classification

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	UniProt
RMND1	NM_017909.4	c.713A>G	p.Asn238Ser	missense_variant	5/12	ENST00000444024.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RMND1	ENST00000444024.3	c.713A>G	p.Asn238Ser	missense_variant	5/12	3	NM_017909.4	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32

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: 50 AN: 249272 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134872

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.: 0 Cov.: 26 AF XY: 0.000375 AC XY: 271 AN XY: 721914

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: 36 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74338

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.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined oxidative phosphorylation defect type 11 Pathogenic:5 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
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	- -

not provided Pathogenic:5

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	26
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	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
REVEL	Pathogenic	0.80
Polyphen		0.99	D;D;.
Vest4		0.94, 0.94
MVP		0.69
MPC		0.71
ClinPred		0.67	D
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

Other links and lift over

dbSNP: rs144972972; hg19: chr6-151751289;