rs35135520
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_StrongPS3PP5_Moderate
The NM_001001563.5(TIMM50):c.26C>A(p.Ser9*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000788332: In vitro functional analysis on skin fibroblasts showed low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential and impaired TIM23-dependent protein import.". Synonymous variant affecting the same amino acid position (i.e. S9S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TIMM50
NM_001001563.5 stop_gained
NM_001001563.5 stop_gained
Scores
2
2
2
Clinical Significance
Conservation
PhyloP100: 0.204
Publications
5 publications found
Genes affected
TIMM50 (HGNC:23656): (translocase of inner mitochondrial membrane 50) This gene encodes a subunit of the TIM23 inner mitochondrial membrane translocase complex. The encoded protein functions as the receptor subunit that recognizes the mitochondrial targeting signal, or presequence, on protein cargo that is destined for the mitochondrial inner membrane and matrix. This protein may also play a role in maintaining the membrane permeability barrier, and knockdown of this gene in human cells results in the release of cytochrome c and apoptosis. [provided by RefSeq, Jul 2016]
TIMM50 Gene-Disease associations (from GenCC):
- 3-methylglutaconic aciduria type 9Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PS3
PS3 evidence extracted from ClinVar submissions: SCV000788332: In vitro functional analysis on skin fibroblasts showed low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential and impaired TIM23-dependent protein import.
PP5
Variant 19-39480879-C-A is Pathogenic according to our data. Variant chr19-39480879-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 559480.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001001563.5. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TIMM50 | TSL:1 MANE Select | c.26C>A | p.Ser9* | stop_gained | Exon 1 of 11 | ENSP00000475531.1 | Q3ZCQ8-1 | ||
| TIMM50 | TSL:1 | c.335C>A | p.Ser112* | stop_gained | Exon 1 of 11 | ENSP00000445806.2 | Q3ZCQ8-2 | ||
| TIMM50 | TSL:1 | n.26C>A | non_coding_transcript_exon | Exon 1 of 10 | ENSP00000472476.2 | M0R2D2 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152266Hom.: 0 Cov.: 34
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GnomAD2 exomes AF: 0.00 AC: 0AN: 218814 AF XY: 0.00
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1447252Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 719532
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African (AFR)
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33300
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Ashkenazi Jewish (ASJ)
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25838
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39310
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85134
European-Finnish (FIN)
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46654
Middle Eastern (MID)
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5588
European-Non Finnish (NFE)
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1108068
Other (OTH)
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59832
GnomAD4 genome 0.00 AC: 0AN: 152384Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74518
GnomAD4 genome
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3472
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5180
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4832
European-Finnish (FIN)
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10632
Middle Eastern (MID)
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294
European-Non Finnish (NFE)
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68040
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2116
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
3-methylglutaconic aciduria type 9 (1)
1
-
-
Mitochondrial encephalopathy (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
PhyloP100
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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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