rs869320665

Variant names:

• chrX-101348591-AC-A
• rs869320665
• NM_004085.4:c.73delG

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.73delG​(p.Val25fs) 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. Fraction of 0.752 CDS is truncated, and there are 0 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 rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.73delG	p.Val25fs	frameshift_variant	Exon 1 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.73delG	p.Val25fs	frameshift_variant	Exon 1 of 2		NP_001139423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM8A	ENST00000372902.4	c.73delG	p.Val25fs	frameshift_variant	Exon 1 of 2	1	NM_004085.4	ENSP00000361993.3
TIMM8A	ENST00000644112.2	c.73delG	p.Val25fs	frameshift_variant	Exon 1 of 2			ENSP00000494385.1
TIMM8A	ENST00000645279.1	n.73delG		non_coding_transcript_exon_variant	Exon 1 of 3			ENSP00000494239.1
TIMM8A	ENST00000647480.1	n.-17delG		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

Apr 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as 108delG. 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. ClinVar contains an entry for this variant (Variation ID: 11322). 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

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;