chr12-123256875-AG-A
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_152269.5(MTRFR):c.346delG(p.Val116fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MTRFR
NM_152269.5 frameshift
NM_152269.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.54
Publications
4 publications found
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: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]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-123256875-AG-A is Pathogenic according to our data. Variant chr12-123256875-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 91408.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_152269.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MTRFR | NM_152269.5 | MANE Select | c.346delG | p.Val116fs | frameshift | Exon 3 of 3 | NP_689482.1 | Q9H3J6-1 | |
| MTRFR | NM_001143905.2 | c.346delG | p.Val116fs | frameshift | Exon 3 of 3 | NP_001137377.1 | Q9H3J6-1 | ||
| MTRFR | NM_001194995.1 | c.346delG | p.Val116fs | frameshift | Exon 3 of 3 | NP_001181924.1 | Q9H3J6-1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MTRFR | ENST00000253233.6 | TSL:1 MANE Select | c.346delG | p.Val116fs | frameshift | Exon 3 of 3 | ENSP00000253233.1 | Q9H3J6-1 | |
| MTRFR | ENST00000366329.7 | TSL:2 | c.346delG | p.Val116fs | frameshift | Exon 3 of 3 | ENSP00000390647.1 | Q9H3J6-1 | |
| MTRFR | ENST00000429587.2 | TSL:2 | c.346delG | p.Val116fs | frameshift | Exon 2 of 2 | ENSP00000391513.2 | Q9H3J6-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461718Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727172 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461718
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727172
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33476
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39688
South Asian (SAS)
AF:
AC:
1
AN:
86244
European-Finnish (FIN)
AF:
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111900
Other (OTH)
AF:
AC:
0
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Combined oxidative phosphorylation defect type 7 (1)
1
-
-
Hereditary spastic paraplegia 55 (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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