X-101346595-G-C

Variant names:

• chrX-101346595-G-C
• rs80356560
• NM_004085.4:c.198C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004085.4(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 NM_004085.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.318
• Publications: 20 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 11321.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.198C>G	p.Cys66Trp	missense_variant	Exon 2 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*1792C>G		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.198C>G	p.Cys66Trp	missense_variant	Exon 2 of 2	1	NM_004085.4	ENSP00000361993.3

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

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jun 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 06, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Benign	0.0	.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;.
PhyloP100		0.32
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.0	.;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Vest4		0.0
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.99
gMVP		1.0
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80356560; hg19: chrX-100601583;