X-101348595-C-G

Position:

• chrX-101348595-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000372902.4(TIMM8A):​c.70G>C​(p.Glu24Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: TIMM8A ENST00000372902.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.62

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.70G>C	p.Glu24Gln	missense_variant	1/2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.70G>C	p.Glu24Gln	missense_variant	1/2		NP_001139423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMM8A	ENST00000372902.4	c.70G>C	p.Glu24Gln	missense_variant	1/2	1	NM_004085.4	ENSP00000361993	P1
TIMM8A	ENST00000644112.2	c.70G>C	p.Glu24Gln	missense_variant	1/2			ENSP00000494385
TIMM8A	ENST00000645279.1	c.70G>C	p.Glu24Gln	missense_variant, NMD_transcript_variant	1/3			ENSP00000494239
TIMM8A	ENST00000647480.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183415 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67865

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;T;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	.;.;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.70	.;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.37	.;.;T;.
Sift4G	Benign	0.37	.;.;T;.
Polyphen		0.23	.;B;B;.
Vest4		0.52
MutPred		0.40		Loss of ubiquitination at K29 (P = 0.1223);Loss of ubiquitination at K29 (P = 0.1223);Loss of ubiquitination at K29 (P = 0.1223);Loss of ubiquitination at K29 (P = 0.1223);
MVP		0.86
MPC		1.1
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.52
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033631; hg19: chrX-100603583;