rs397515421

Positions:

chr6-151405787-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_017909.4(RMND1):c.1250G>A(p.Arg417Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RMND1
NM_017909.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.51

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:

RMND1 (HGNC:):

RMND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-151405787-C-T is Pathogenic according to our data. Variant chr6-151405787-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RMND1	NM_017909.4 linkuse as main transcript	c.1250G>A	p.Arg417Gln	missense_variant	11/12	ENST00000444024.3	NP_060379.2	Q9NWS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMND1	ENST00000444024.3 linkuse as main transcript	c.1250G>A	p.Arg417Gln	missense_variant	11/12	3	NM_017909.4	ENSP00000412708.2		Q9NWS8-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251198

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460544

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 11

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 15, 2021	- -

Mitochondrial disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Dec 22, 2015

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters RMND1 gene expression (PMID: 23022098, 25604853, 26238252). 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) performed at Invitae indicates that this missense variant is expected to disrupt RMND1 protein function. ClinVar contains an entry for this variant (Variation ID: 39765). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 23022098, 26238252, 27412952). 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. This variant is present in population databases (rs397515421, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 417 of the RMND1 protein (p.Arg417Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.013

T;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Uncertain

-0.040

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.1

.;N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.019

.;D;.

Sift4G

Benign

0.090

.;T;T

Polyphen

1.0

D;D;.

Vest4

0.93, 0.95

MutPred

0.43

Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);.;

MVP

0.72

MPC

0.87

ClinPred

0.71

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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