X-101346511-G-T

Variant names:

• chrX-101346511-G-T
• rs1443740723
• NM_004085.4:c.282C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.282C>A	p.Ser94Arg	missense_variant	Exon 2 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*1876C>A		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	c.282C>A	p.Ser94Arg	missense_variant	Exon 2 of 2	1	NM_004085.4	ENSP00000361993.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097279 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363157

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	0.0049	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	.;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.48	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.71	.;N
REVEL	Benign	0.28
Sift	Benign	0.076	.;T
Sift4G	Benign	0.31	.;T
Polyphen		0.0010	B;B
Vest4		0.49
MutPred		0.094		Loss of phosphorylation at S94 (P = 0.0173);Loss of phosphorylation at S94 (P = 0.0173);
MVP		0.88
MPC		1.2
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.37
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs1443740723; hg19: chrX-100601499;