X-101346683-T-G

Position:

• chrX-101346683-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000372902.4(TIMM8A):​c.133-23A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 23)
• Consequence: TIMM8A ENST00000372902.4 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.718

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101346683-T-G is Pathogenic according to our data. Variant chrX-101346683-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11325.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101346683-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.133-23A>C		intron_variant		ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*1704A>C		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.133-23A>C		intron_variant		1	NM_004085.4	ENSP00000361993	P1
TIMM8A	ENST00000644112.2	c.*1704A>C		3_prime_UTR_variant	2/2			ENSP00000494385
TIMM8A	ENST00000645279.1	c.*327-23A>C		intron_variant, NMD_transcript_variant				ENSP00000494239
TIMM8A	ENST00000647480.1	n.650-23A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Deafness dystonia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.72
La Branchor		0.88
BranchPoint Hunter		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 11

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320666; hg19: chrX-100601671;