rs576462794

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_152269.5(MTRFR):c.210delA(p.Gly72AlafsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

MTRFR
NM_152269.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: -3.37

Variant links:

Genes affected

MTRFR (HGNC:26784): (mitochondrial translation release factor in rescue) This nuclear gene encodes a mitochondrial matrix protein that appears to contribute to peptide chain termination in the mitochondrial translation machinery. Two different 1 bp deletions (resulting in the same premature stop codon)result in decreased mitochondrial translation, decreased levels of oxidative phosphorylation complexes and encepthalomyopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

MTRFR links:

CDK2AP1 (HGNC:14002): (cyclin dependent kinase 2 associated protein 1) The protein encoded by this gene is a cyclin-dependent kinase 2 (CDK2) -associated protein which is thought to negatively regulate CDK2 activity by sequestering monomeric CDK2, and targeting CDK2 for proteolysis. This protein was found to also interact with DNA polymerase alpha/primase and mediate the phosphorylation of the large p180 subunit, which suggests a regulatory role in DNA replication during the S-phase of the cell cycle. This protein also forms a core subunit of the nucleosome remodeling and histone deacetylation (NURD) complex that epigenetically regulates embryonic stem cell differentiation. This gene thus plays a role in both cell-cycle and epigenetic regulation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2012]

CDK2AP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-123253883-CA-C is Pathogenic according to our data. Variant chr12-123253883-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123253883-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRFR	NM_152269.5 link	c.210delA	p.Gly72AlafsTer13	frameshift_variant	Exon 2 of 3	ENST00000253233.6	NP_689482.1	Q9H3J6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRFR	ENST00000253233.6 link	c.210delA	p.Gly72AlafsTer13	frameshift_variant	Exon 2 of 3	1	NM_152269.5	ENSP00000253233.1		Q9H3J6-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152190

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251348

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

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:

0.000378

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000224

AC:

327

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

160

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000283

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000158

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74484

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:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.000102

EpiCase

AF:

0.000491

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Sep 23, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MTRFR: PVS1, PM2, PM3 -

Jul 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 95 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 20598281, 24284555, 27858754, 30609409, 36344503) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM2, PM3, PVS1 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Combined oxidative phosphorylation defect type 7

Pathogenic:4Other:1

Jul 09, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 23, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The C12orf65 c.210delA (p.Gly72AlafsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly72AlafsTer13 variant has been reported in three studies and is found in four probands with combined oxidative phosphorylation deficiency (COXPD) including in two in a homozygous state and in two siblings in a compound heterozygous state (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00032 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Gly72AlafsTer13 variant resulted in reduced complex IV activity and reduced quantities of complex I, IV, and V in proband fibroblasts (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Based on the potential impact of frameshift variants and available evidence, the p.Gly72AlafsTer13 variant is classified as pathogenic for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 19, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly72AlafsX13 variant in C12orf65 has been reported in 2 homozygous and 1 compound heterozygous probands with clinical features of combined oxidative phos phorylation deficiency type 7 (COXPD7) and segregated with disease in one additi onal affected sibling (Antonika 2010, Heidary 2013, Wesolowska 2015). This varia nt has also been identified in 1/8254 of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs57646274). This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 72 and leads to a premature termination codon 1 3 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Biallelic loss of function of the C12orf65 gene has been a ssociated with COXPD7. In summary, this variant meets criteria to be classified as pathogenic for COXPD7 in an autosomal recessive manner based upon its occurr ence in affected individuals and predicted functional impact. -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 10-10-2014 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 19, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: C12orf65 c.210delA (p.Gly72AlafsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. One study of C12orf65 mRNA from a homozygous patient showed the level of the C12orf65 mRNA was not significantly reduced, suggesting that nonsense-mediated mRNA decay does not contribute to the loss of function of the C12orf65 gene product (Antonicka_2010). Truncations downstream of this position have been reported with various Mitochondrial disorders in HGMD. The variant allele was found at a frequency of 0.00018 in 251348 control chromosomes. c.210delA has been reported in the literature in multiple individuals affected mitochondrial disorders including Leigh syndrome, optic atrophy, and ophthalmoplegia (examples: Antonicka_2010, Heidary_2014, Wesolowska_2015, Schon_2021). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7

Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly72Alafs*13) in the C12orf65 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the C12orf65 protein. This variant is present in population databases (rs576462794, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of C12orf65-related conditions (PMID: 20598281, 24284555, 27858754). 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: 54). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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