3-119500730-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_016589.4(TIMMDC1):c.230T>C(p.Ile77Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000768 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
TIMMDC1
NM_016589.4 missense
NM_016589.4 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 4.23
Genes affected
TIMMDC1 (HGNC:1321): (translocase of inner mitochondrial membrane domain containing 1) Located in mitochondrion and nucleoplasm. Implicated in nuclear type mitochondrial complex I deficiency 31. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000368 (56/152318) while in subpopulation AFR AF= 0.00123 (51/41564). AF 95% confidence interval is 0.000958. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TIMMDC1 | NM_016589.4 | c.230T>C | p.Ile77Thr | missense_variant | 2/7 | ENST00000494664.6 | |
TIMMDC1 | XM_017006556.2 | c.194+1803T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TIMMDC1 | ENST00000494664.6 | c.230T>C | p.Ile77Thr | missense_variant | 2/7 | 1 | NM_016589.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000368 AC: 56AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000112 AC: 28AN: 250750Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135508
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461402Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727004
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GnomAD4 genome ? AF: 0.000368 AC: 56AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74484
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2021 | The c.230T>C (p.I77T) alteration is located in exon 2 (coding exon 2) of the TIMMDC1 gene. This alteration results from a T to C substitution at nucleotide position 230, causing the isoleucine (I) at amino acid position 77 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 77 of the TIMMDC1 protein (p.Ile77Thr). This variant is present in population databases (rs139467319, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with TIMMDC1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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