X-101346587-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004085.4(TIMM8A):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

TIMM8A
NM_004085.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.75

Variant links:

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]

TIMM8A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM8A	NM_004085.4 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	2/2	ENST00000372902.4
TIMM8A	NM_001145951.2 linkuse as main transcript	c.*1800G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TIMM8A	ENST00000372902.4 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	2/2	1	NM_004085.4	P1
TIMM8A	ENST00000644112.2 linkuse as main transcript	c.*1800G>A		3_prime_UTR_variant	2/2
TIMM8A	ENST00000647480.1 linkuse as main transcript	n.723G>A		non_coding_transcript_exon_variant	2/2
TIMM8A	ENST00000645279.1 linkuse as main transcript	c.*400G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183489

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67921

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1098145

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363509

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2023

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This variant has not been reported in the literature in individuals affected with TIMM8A-related conditions. This variant is present in population databases (rs781878654, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 69 of the TIMM8A protein (p.Arg69His). 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.47

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

Polyphen

0.29

B;B

Vest4

0.76

MutPred

0.92

Loss of stability (P = 0.0733);Loss of stability (P = 0.0733);

MVP

0.96

MPC

1.5

ClinPred

0.88

GERP RS

5.3

Varity_R

0.67

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over