dbSNP rs180806413: TIMM8A:c.-6C>T (chrX-101348670-G-A) – 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.-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

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=-0.85).

BP6

Variant X-101348670-G-A is Benign according to our data. Variant chrX-101348670-G-A is described in ClinVar as Benign. ClinVar VariationId is 137659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 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.-6C>T		5_prime_UTR	Exon 1 of 2	NP_004076.1	O60220
	TIMM8A	NM_001145951.2		c.-6C>T		5_prime_UTR	Exon 1 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.-6C>T	5_prime_UTR	Exon 1 of 2	ENSP00000361993.3	O60220
TIMM8A	ENST00000940410.1		c.-6C>T	5_prime_UTR	Exon 1 of 2	ENSP00000610469.1
TIMM8A	ENST00000940411.1		c.-6C>T	5_prime_UTR	Exon 1 of 2	ENSP00000610470.1

Frequencies

GnomAD3 genomes

AF:

0.00709

AC:

791

AN:

111573

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00687

AC:

1257

AN:

183064

AF XY:

0.00694

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 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

African (AFR)

AF:

0.00133

AC:

AN:

26377

American (AMR)

AF:

0.00290

AC:

102

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.000620

AC:

AN:

19367

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30180

South Asian (SAS)

AF:

0.000813

AC:

AN:

54109

European-Finnish (FIN)

AF:

0.00594

AC:

240

AN:

40421

Middle Eastern (MID)

AF:

0.000817

AC:

AN:

3670

European-Non Finnish (NFE)

AF:

0.0132

AC:

11077

AN:

841790

Other (OTH)

AF:

0.00917

AC:

422

AN:

46027

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

499

997

1496

1994

2493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.00709

AC:

791

AN:

111631

Hom.:

Cov.:

AF XY:

0.00635

AC XY:

215

AN XY:

33851

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

30797

American (AMR)

AF:

0.00474

AC:

AN:

10538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3525

South Asian (SAS)

AF:

0.000376

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.00483

AC:

AN:

5999

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0121

AC:

644

AN:

53048

Other (OTH)

AF:

0.00923

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00654

EpiCase

AF:

0.0109

EpiControl

AF:

0.0110

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.48

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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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