rs180806413

Positions:

chrX-101348670-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004085.4(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
NM_004085.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.479

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 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 linkuse as main transcript	c.-6C>T		5_prime_UTR_variant	1/2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2 linkuse as main transcript	c.-6C>T		5_prime_UTR_variant	1/2		NP_001139423.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TIMM8A	ENST00000372902.4 linkuse as main transcript	c.-6C>T	5_prime_UTR_variant	1/2	1	NM_004085.4	ENSP00000361993.3	O60220
TIMM8A	ENST00000644112.2 linkuse as main transcript	c.-6C>T	5_prime_UTR_variant	1/2			ENSP00000494385.1	A0A2R8YDA8
TIMM8A	ENST00000645279.1 linkuse as main transcript	n.-6C>T	non_coding_transcript_exon_variant	1/3			ENSP00000494239.1	A0A2R8YDA8
TIMM8A	ENST00000645279.1 linkuse as main transcript	n.-6C>T	5_prime_UTR_variant	1/3			ENSP00000494239.1	A0A2R8YDA8

Frequencies

GnomAD3 genomes

AF:

0.00709

AC:

791

AN:

111573

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

215

AN XY:

33783

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00475

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.00483

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00935

GnomAD3 exomes

AF:

0.00687

AC:

1257

AN:

183064

Hom.:

AF XY:

0.00694

AC XY:

469

AN XY:

67592

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000786

Gnomad FIN exome

AF:

0.00660

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00839

GnomAD4 exome

AF:

0.0109

AC:

11936

AN:

1097125

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

3775

AN XY:

362707

show subpopulations

Gnomad4 AFR exome

AF:

0.00133

Gnomad4 AMR exome

AF:

0.00290

Gnomad4 ASJ exome

AF:

0.000620

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000813

Gnomad4 FIN exome

AF:

0.00594

Gnomad4 NFE exome

AF:

0.0132

Gnomad4 OTH exome

AF:

0.00917

GnomAD4 genome

AF:

0.00709

AC:

791

AN:

111631

Hom.:

Cov.:

AF XY:

0.00635

AC XY:

215

AN XY:

33851

show subpopulations

Gnomad4 AFR

AF:

0.00169

Gnomad4 AMR

AF:

0.00474

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000376

Gnomad4 FIN

AF:

0.00483

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00923

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00654

EpiCase

AF:

0.0109

EpiControl

AF:

0.0110

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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

DANN

Benign

0.90

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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