rs869320665

Positions:

• chrX-101348591-AC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004085.4(TIMM8A):​c.73del​(p.Val25Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TIMM8A NM_004085.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.15

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101348591-AC-A is Pathogenic according to our data. Variant chrX-101348591-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 11322.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101348591-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM8A	NM_004085.4	c.73del	p.Val25Ter	frameshift_variant	1/2	ENST00000372902.4
TIMM8A	NM_001145951.2	c.73del	p.Val25Ter	frameshift_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMM8A	ENST00000372902.4	c.73del	p.Val25Ter	frameshift_variant	1/2	1	NM_004085.4	P1
TIMM8A	ENST00000644112.2	c.73del	p.Val25Ter	frameshift_variant	1/2
TIMM8A	ENST00000645279.1	c.73del	p.Val25Ter	frameshift_variant, NMD_transcript_variant	1/3
TIMM8A	ENST00000647480.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2023

ClinVar contains an entry for this variant (Variation ID: 11322). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as 108delG. This premature translational stop signal has been observed in individual(s) with Mohr-Tranebjaerg syndrome (PMID: 11601506). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val25*) in the TIMM8A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TIMM8A are known to be pathogenic (PMID: 11956200, 21984432, 22736418). -

Deafness dystonia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

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: rs869320665; hg19: chrX-100603579;