NM_004085.4:c.232_233insCAAT

Variant names:

• chrX-101346560-A-AATTG
• NM_004085.4:c.232_233insCAAT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004085.4(TIMM8A):​c.232_233insCAAT​(p.Leu78SerfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TIMM8A NM_004085.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.44

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 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.211 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-101346560-A-AATTG is Pathogenic according to our data. Variant chrX-101346560-A-AATTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1185678.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.232_233insCAAT	p.Leu78SerfsTer21	frameshift_variant	Exon 2 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*1826_*1827insCAAT		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.232_233insCAAT	p.Leu78SerfsTer21	frameshift_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:1

Revision: no assertion criteria provided

Submissions by phenotype

Deafness dystonia syndrome Pathogenic:1

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Deafness Molecular Diagnostic Center, Chinese PLA General Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100601548;