Genetic Variant TIMM8A:p.Asp72Asp (chrX-101346577-A-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004085.4(TIMM8A):c.216T>C(p.Asp72Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.000154 in 1,210,411 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 56 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00016 ( 0 hom. 55 hem. )

Consequence

TIMM8A
NM_004085.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.59

Publications

1 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: Ambry Genetics, PanelApp Australia, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

TIMM8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant X-101346577-A-G is Benign according to our data. Variant chrX-101346577-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1193516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 55 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004085.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM8A	NM_004085.4	MANE Select	c.216T>C	p.Asp72Asp	synonymous	Exon 2 of 2	NP_004076.1	O60220
	TIMM8A	NM_001145951.2		c.*1810T>C		3_prime_UTR	Exon 2 of 2	NP_001139423.1	A0A2R8YDA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMM8A	ENST00000372902.4	TSL:1 MANE Select	c.216T>C	p.Asp72Asp	synonymous	Exon 2 of 2	ENSP00000361993.3	O60220
TIMM8A	ENST00000940410.1		c.219T>C	p.Asp73Asp	synonymous	Exon 2 of 2	ENSP00000610469.1
TIMM8A	ENST00000940411.1		c.210T>C	p.Asp70Asp	synonymous	Exon 2 of 2	ENSP00000610470.1

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112237

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000938

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183515

AF XY:

0.0000589

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000732

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000164

AC:

180

AN:

1098174

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

363542

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4085

European-Non Finnish (NFE)

AF:

0.000210

AC:

177

AN:

842130

Other (OTH)

AF:

0.0000434

AC:

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000535

AC:

AN:

112237

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34377

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30914

American (AMR)

AF:

0.00

AC:

AN:

10541

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3598

South Asian (SAS)

AF:

0.00

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000938

AC:

AN:

53281

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

4.6

Mutation Taster

=73/27

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over