rs576462794

Positions:

• chr12-123253883-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_152269.5(MTRFR):​c.210delA​(p.Gly72fs) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: -3.37

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]

CDK2AP1 (HGNC:):

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]

ACMG classification

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/exons	MANE	Protein	UniProt
MTRFR	NM_152269.5	c.210delA	p.Gly72fs	frameshift_variant	2/3	ENST00000253233.6	NP_689482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTRFR	ENST00000253233.6	c.210delA	p.Gly72fs	frameshift_variant	2/3	1	NM_152269.5	ENSP00000253233.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152190 Hom.: 0 Cov.: 31

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: 44 AN: 251348 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135874

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.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 160 AN XY: 727244

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: 24 AN: 152308 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74484

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.: 0

Bravo AF: 0.000102

EpiCase AF: 0.000491

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 17, 2021	PP1, PM2, PM3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MTRFR: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2023	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) -

Combined oxidative phosphorylation defect type 7 Pathogenic:4 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 23, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2016	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 09, 2010	- -

Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

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

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

Other links and lift over

dbSNP: rs576462794; hg19: chr12-123738430;