rs180806413
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The ENST00000372902.4(TIMM8A):c.-6C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,208,756 control chromosomes in the GnomAD database, including 53 homozygotes. There are 3,990 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0071 ( 5 hom., 215 hem., cov: 22)
Exomes 𝑓: 0.011 ( 48 hom. 3775 hem. )
Consequence
TIMM8A
ENST00000372902.4 5_prime_UTR
ENST00000372902.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.479
Genes affected
TIMM8A (HGNC:11817): (translocase of inner mitochondrial membrane 8A) This translocase is involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in Mohr-Tranebjaerg syndrome/Deafness Dystonia Syndrome (MTS/DDS) and it is postulated that MTS/DDS is a mitochondrial disease caused by a defective mitochondrial protein import system. Defects in this gene also cause Jensen syndrome; an X-linked disease with opticoacoustic nerve atrophy and muscle weakness. This protein, along with TIMM13, forms a 70 kDa heterohexamer. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant X-101348670-G-A is Benign according to our data. Variant chrX-101348670-G-A is described in ClinVar as [Benign]. Clinvar id is 137659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101348670-G-A is described in Lovd as [Benign]. Variant chrX-101348670-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAd4 at 5 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TIMM8A | NM_004085.4 | c.-6C>T | 5_prime_UTR_variant | 1/2 | ENST00000372902.4 | NP_004076.1 | ||
TIMM8A | NM_001145951.2 | c.-6C>T | 5_prime_UTR_variant | 1/2 | NP_001139423.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TIMM8A | ENST00000372902.4 | c.-6C>T | 5_prime_UTR_variant | 1/2 | 1 | NM_004085.4 | ENSP00000361993 | P1 | ||
TIMM8A | ENST00000644112.2 | c.-6C>T | 5_prime_UTR_variant | 1/2 | ENSP00000494385 | |||||
TIMM8A | ENST00000645279.1 | c.-6C>T | 5_prime_UTR_variant, NMD_transcript_variant | 1/3 | ENSP00000494239 |
Frequencies
GnomAD3 genomes AF: 0.00709 AC: 791AN: 111573Hom.: 5 Cov.: 22 AF XY: 0.00636 AC XY: 215AN XY: 33783
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GnomAD3 exomes AF: 0.00687 AC: 1257AN: 183064Hom.: 2 AF XY: 0.00694 AC XY: 469AN XY: 67592
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GnomAD4 exome AF: 0.0109 AC: 11936AN: 1097125Hom.: 48 Cov.: 33 AF XY: 0.0104 AC XY: 3775AN XY: 362707
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GnomAD4 genome AF: 0.00709 AC: 791AN: 111631Hom.: 5 Cov.: 22 AF XY: 0.00635 AC XY: 215AN XY: 33851
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | -6C>T in Exon 01 of TIMM8A: This variant is not expected to have clinical signif icance because it has been identified in 1.0% (58/5545) of European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washingto - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 23, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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