rs80356560

Positions:

• chrX-101346595-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The ENST00000372902.4(TIMM8A):​c.198C>G​(p.Cys66Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TIMM8A ENST00000372902.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.318

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-101346595-G-C is Pathogenic according to our data. Variant chrX-101346595-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11321.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101346595-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.198C>G	p.Cys66Trp	missense_variant	2/2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*1792C>G		3_prime_UTR_variant	2/2		NP_001139423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMM8A	ENST00000372902.4	c.198C>G	p.Cys66Trp	missense_variant	2/2	1	NM_004085.4	ENSP00000361993	P1
TIMM8A	ENST00000644112.2	c.*1792C>G		3_prime_UTR_variant	2/2			ENSP00000494385
TIMM8A	ENST00000647480.1	n.715C>G		non_coding_transcript_exon_variant	2/2
TIMM8A	ENST00000645279.1	c.*392C>G		3_prime_UTR_variant, NMD_transcript_variant	3/3			ENSP00000494239

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deafness dystonia syndrome Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-11	.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.95		Gain of MoRF binding (P = 0.2629);Gain of MoRF binding (P = 0.2629);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.99
gMVP		1.0

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: rs80356560; hg19: chrX-100601583;