NM_004085.4:c.132+158A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004085.4(TIMM8A):c.132+158A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,172,658 control chromosomes in the GnomAD database, including 160 homozygotes. There are 6,494 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 11 hom., 401 hem., cov: 21)

Exomes 𝑓: 0.018 ( 149 hom. 6093 hem. )

Consequence

TIMM8A
NM_004085.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.327

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

deafness dystonia syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen

TIMM8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant X-101348375-T-C is Benign according to our data. Variant chrX-101348375-T-C is described in ClinVar as Benign. ClinVar VariationId is 44082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1348/110006) while in subpopulation NFE AF = 0.0177 (929/52607). AF 95% confidence interval is 0.0167. There are 11 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4 link	c.132+158A>G		intron_variant	Intron 1 of 1	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2 link	c.*12A>G		3_prime_UTR_variant	Exon 2 of 2		NP_001139423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM8A	ENST00000372902.4 link	c.132+158A>G		intron_variant	Intron 1 of 1	1	NM_004085.4	ENSP00000361993.3		O60220

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1348

AN:

109950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00206

Gnomad AMI

AF:

0.0613

Gnomad AMR

AF:

0.00938

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0248

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.0177

Gnomad OTH

AF:

0.00605

GnomAD2 exomes

AF:

0.0136

AC:

1669

AN:

122550

AF XY:

0.0134

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00662

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0229

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.0175

AC:

18633

AN:

1062652

Hom.:

149

Cov.:

AF XY:

0.0176

AC XY:

6093

AN XY:

347068

show subpopulations

African (AFR)

AF:

0.00153

AC:

AN:

25414

American (AMR)

AF:

0.00619

AC:

176

AN:

28455

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

245

AN:

18747

East Asian (EAS)

AF:

0.0000717

AC:

AN:

27906

South Asian (SAS)

AF:

0.0131

AC:

662

AN:

50699

European-Finnish (FIN)

AF:

0.0249

AC:

954

AN:

38285

Middle Eastern (MID)

AF:

0.00878

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.0192

AC:

15811

AN:

824219

Other (OTH)

AF:

0.0158

AC:

708

AN:

44829

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

678

1356

2033

2711

3389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

596

1192

1788

2384

2980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1348

AN:

110006

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

401

AN XY:

32342

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

30201

American (AMR)

AF:

0.00936

AC:

AN:

10359

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

2631

East Asian (EAS)

AF:

0.000577

AC:

AN:

3464

South Asian (SAS)

AF:

0.0103

AC:

AN:

2535

European-Finnish (FIN)

AF:

0.0248

AC:

144

AN:

5817

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0177

AC:

929

AN:

52607

Other (OTH)

AF:

0.00597

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0145

Hom.:

115

Bravo

AF:

0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 03, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

*12A>G in Exon 02 of TIMM8A: This variant is not expected to have clinical signi ficance because it has been identified in 1.6% (30/1899) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs41309506). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.33

PromoterAI

0.054

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over