rs41309506

Variant names:

Variant summary

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

The NM_001145951.2(TIMM8A):c.*12A>G variant causes a 3 prime UTR 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_001145951.2 3_prime_UTR

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

TIMM8A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001145951.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145951.2. 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.132+158A>G		intron	N/A	NP_004076.1	O60220
	TIMM8A	NM_001145951.2		c.*12A>G		3_prime_UTR	Exon 2 of 2	NP_001139423.1	A0A2R8YDA8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TIMM8A	ENST00000372902.4	TSL:1 MANE Select	c.132+158A>G	intron	N/A	ENSP00000361993.3	O60220
TIMM8A	ENST00000644112.2		c.*12A>G	3_prime_UTR	Exon 2 of 2	ENSP00000494385.1	A0A2R8YDA8
TIMM8A	ENST00000940410.1		c.132+158A>G	intron	N/A	ENSP00000610469.1

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over