rs869320666

Variant names:

• chrX-101346683-T-G
• rs869320666
• NM_004085.4:c.133-23A>C

Variant summary

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

The NM_001145951.2(TIMM8A):​c.*1704A>C variant causes a 3 prime UTR 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).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TIMM8A NM_001145951.2 3_prime_UTR
• 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 rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.133-23A>C		intron_variant	Intron 1 of 1	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*1704A>C		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.133-23A>C		intron_variant	Intron 1 of 1	1	NM_004085.4	ENSP00000361993.3
TIMM8A	ENST00000644112	c.*1704A>C		3_prime_UTR_variant	Exon 2 of 2			ENSP00000494385.1
TIMM8A	ENST00000645279.1	n.*327-23A>C		intron_variant	Intron 2 of 2			ENSP00000494239.1
TIMM8A	ENST00000647480.1	n.650-23A>C		intron_variant	Intron 1 of 1

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

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;