11-112086722-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_012459.4(TIMM8B):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,602,506 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.0000062 ( 1 hom. )
Consequence
TIMM8B
NM_012459.4 start_lost
NM_012459.4 start_lost
Scores
3
6
8
Clinical Significance
Conservation
PhyloP100: 3.15
Genes affected
TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TIMM8B | ENST00000504148.3 | c.2T>C | p.Met1? | start_lost | 1/2 | 1 | NM_012459.4 | ENSP00000422122.2 | ||
TIMM8B | ENST00000541231.1 | c.47T>C | p.Met16Thr | missense_variant | 1/2 | 1 | ENSP00000438455.1 | |||
TIMM8B | ENST00000509359.6 | n.2T>C | non_coding_transcript_exon_variant | 1/3 | 1 | ENSP00000421964.2 | ||||
TIMM8B | ENST00000507614.1 | n.1T>C | non_coding_transcript_exon_variant | 1/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000130 AC: 3AN: 230978Hom.: 0 AF XY: 0.00000797 AC XY: 1AN XY: 125416
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GnomAD4 exome AF: 0.00000621 AC: 9AN: 1450316Hom.: 1 Cov.: 32 AF XY: 0.00000416 AC XY: 3AN XY: 721090
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | The c.47T>C (p.M16T) alteration is located in exon 1 (coding exon 1) of the TIMM8B gene. This alteration results from a T to C substitution at nucleotide position 47, causing the methionine (M) at amino acid position 16 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MVP
MPC
0.048
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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