X-101346594-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_004085.4(TIMM8A):c.199G>A(p.Val67Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,210,333 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

TIMM8A
NM_004085.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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_benign. Variant got -1 ACMG points.

BP6

Variant X-101346594-C-T is Benign according to our data. Variant chrX-101346594-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1178826.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM8A	NM_004085.4 linkuse as main transcript	c.199G>A	p.Val67Ile	missense_variant	2/2	ENST00000372902.4
TIMM8A	NM_001145951.2 linkuse as main transcript	c.*1793G>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.199G>A	p.Val67Ile	missense_variant	2/2	1	NM_004085.4	P1
TIMM8A	ENST00000644112.2 linkuse as main transcript	c.*1793G>A		3_prime_UTR_variant	2/2
TIMM8A	ENST00000647480.1 linkuse as main transcript	n.716G>A		non_coding_transcript_exon_variant	2/2
TIMM8A	ENST00000645279.1 linkuse as main transcript	c.*393G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112147

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34303

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183464

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000546

AC:

AN:

1098186

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112147

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34303

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 19, 2021	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 67 of the TIMM8A protein (p.Val67Ile). 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. 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: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 1178826). This variant has not been reported in the literature in individuals affected with TIMM8A-related conditions. This variant is present in population databases (rs782529395, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.20

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

Polyphen

0.45

B;B

Vest4

0.16

MutPred

0.56

Gain of catalytic residue at V67 (P = 0.3371);Gain of catalytic residue at V67 (P = 0.3371);

MVP

0.86

MPC

1.2

ClinPred

0.68

GERP RS

5.3

Varity_R

0.54

gMVP

0.96

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