chrX-101346625-G-A

Variant names:

• chrX-101346625-G-A
• rs1926075797
• NM_004085.4:c.168C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004085.4(TIMM8A):​c.168C>T​(p.Asp56Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000892 in 112,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: TIMM8A NM_004085.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.84
• Publications: 0 publications found

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]

TIMM8A Gene-Disease associations (from GenCC):

• deafness dystonia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-101346625-G-A is Benign according to our data. Variant chrX-101346625-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1778100.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004085.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM8A	NM_004085.4	MANE Select	c.168C>T	p.Asp56Asp	synonymous	Exon 2 of 2	NP_004076.1	O60220
	TIMM8A	NM_001145951.2		c.*1762C>T		3_prime_UTR	Exon 2 of 2	NP_001139423.1	A0A2R8YDA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM8A	ENST00000372902.4	TSL:1 MANE Select	c.168C>T	p.Asp56Asp	synonymous	Exon 2 of 2	ENSP00000361993.3	O60220
	TIMM8A	ENST00000940410.1		c.171C>T	p.Asp57Asp	synonymous	Exon 2 of 2	ENSP00000610469.1
	TIMM8A	ENST00000940411.1		c.162C>T	p.Asp54Asp	synonymous	Exon 2 of 2	ENSP00000610470.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112143 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112143 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34313

African (AFR) AF: 0.0000324 AC: 1 AN: 30909

American (AMR) AF: 0.00 AC: 0 AN: 10523

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2695

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53264

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1926075797; hg19: chrX-100601613;