NM_004085.4:c.282C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_004085.4(TIMM8A):c.282C>A(p.Ser94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

TIMM8A
NM_004085.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.69

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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity TIM8A_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20489946).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM8A	NM_004085.4	MANE Select	c.282C>A	p.Ser94Arg	missense	Exon 2 of 2	NP_004076.1
	TIMM8A	NM_001145951.2		c.*1876C>A		3_prime_UTR	Exon 2 of 2	NP_001139423.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TIMM8A	ENST00000372902.4	TSL:1 MANE Select	c.282C>A	p.Ser94Arg	missense	Exon 2 of 2	ENSP00000361993.3
TIMM8A	ENST00000645279.1		n.*476C>A		non_coding_transcript_exon	Exon 3 of 3	ENSP00000494239.1
TIMM8A	ENST00000647480.1		n.799C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1097279

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363157

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26371

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3422

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842043

Other (OTH)

AF:

0.00

AC:

AN:

46024

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser94Arg variant in TIMM8A has not been previously reported in individuals with hearing loss or Mohr-Tranebjaerg syndrome or in large population studies. Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In summary, the clinical signifi cance of the p.Ser94Arg variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

0.0049

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.48

PhyloP100

2.7

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.71

REVEL

Benign

0.28

Sift

Benign

0.076

Sift4G

Benign

0.31

Polyphen

0.0010

Vest4

0.49

MutPred

0.094

Loss of phosphorylation at S94 (P = 0.0173)

MVP

0.88

MPC

1.2

ClinPred

0.97

GERP RS

3.5

Varity_R

0.37

gMVP

0.88

Mutation Taster

=69/31

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over