Genetic Variant TIMM8A:c.*503_*505dupGAT (chrX-101345993-G-GATC) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_004085.4(TIMM8A):c.*503_*505dupGAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.37 ( 8763 hom., 11391 hem., cov: 11)

Exomes 𝑓: 0.18 ( 10090 hom. 33384 hem. )

Failed GnomAD Quality Control

Consequence

TIMM8A
NM_004085.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.37

Publications

0 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 -9 ACMG points.

BP6

Variant X-101345993-G-GATC is Benign according to our data. Variant chrX-101345993-G-GATC is described in ClinVar as Benign. ClinVar VariationId is 21394.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4 link	c.503_505dupGAT		3_prime_UTR_variant	Exon 2 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2 link	c.2391_2393dupGAT		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.503_505dupGAT		3_prime_UTR_variant	Exon 2 of 2	1	NM_004085.4	ENSP00000361993.3		O60220

Frequencies

GnomAD3 genomes

AF:

0.369

AC:

40476

AN:

109769

Hom.:

8757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.804

Gnomad AMI

AF:

0.0948

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.437

Gnomad SAS

AF:

0.441

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.186

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.315

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.177

AC:

113854

AN:

642029

Hom.:

10090

Cov.:

AF XY:

0.174

AC XY:

33384

AN XY:

191905

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.844

AC:

10357

AN:

12275

American (AMR)

AF:

0.422

AC:

591

AN:

1400

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

644

AN:

4018

East Asian (EAS)

AF:

0.442

AC:

1390

AN:

3144

South Asian (SAS)

AF:

0.447

AC:

5442

AN:

12182

European-Finnish (FIN)

AF:

0.159

AC:

AN:

452

Middle Eastern (MID)

AF:

0.177

AC:

195

AN:

1100

European-Non Finnish (NFE)

AF:

0.154

AC:

90218

AN:

586246

Other (OTH)

AF:

0.233

AC:

4945

AN:

21212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

Heterozygous variant carriers

2920

5840

8761

11681

14601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4788

9576

14364

19152

23940

<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:

0.369

AC:

40540

AN:

109823

Hom.:

8763

Cov.:

AF XY:

0.354

AC XY:

11391

AN XY:

32193

show subpopulations

African (AFR)

AF:

0.804

AC:

24078

AN:

29950

American (AMR)

AF:

0.366

AC:

3737

AN:

10213

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

407

AN:

2630

East Asian (EAS)

AF:

0.437

AC:

1494

AN:

3417

South Asian (SAS)

AF:

0.440

AC:

1130

AN:

2567

European-Finnish (FIN)

AF:

0.152

AC:

885

AN:

5807

Middle Eastern (MID)

AF:

0.199

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.156

AC:

8222

AN:

52845

Other (OTH)

AF:

0.319

AC:

481

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

608

1217

1825

2434

3042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.306

Hom.:

1886

Bravo

AF:

0.414

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Deafness dystonia syndrome

Benign:1

Feb 06, 2003

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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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