NM_004085.4:c.*503_*505dupGAT

Variant names:

• chrX-101345993-G-GATC
• rs4024308
• NM_004085.4:c.*503_*505dupGAT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_004085.4(TIMM8A):​c.*503_*505dupGAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.37 (8763 hom., 11391 hem., cov: 11)
  • Exomes 𝑓: 0.18 (10090 hom. 33384 hem.)
  • Failed GnomAD Quality Control
• Consequence: TIMM8A NM_004085.4 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.37
• 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: PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant X-101345993-G-GATC is Benign according to our data. Variant chrX-101345993-G-GATC is described in ClinVar as Benign. ClinVar VariationId is 21394.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.*503_*505dupGAT		3_prime_UTR_variant	Exon 2 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*2391_*2393dupGAT		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.*503_*505dupGAT		3_prime_UTR_variant	Exon 2 of 2	1	NM_004085.4	ENSP00000361993.3

Frequencies

GnomAD3 genomes AF: 0.369 AC: 40476 AN: 109769 Hom.: 8757 Cov.: 11

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.0948

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.186

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.315

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.177 AC: 113854 AN: 642029 Hom.: 10090 Cov.: 19 AF XY: 0.174 AC XY: 33384 AN XY: 191905

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.844 AC: 10357 AN: 12275

American (AMR) AF: 0.422 AC: 591 AN: 1400

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 644 AN: 4018

East Asian (EAS) AF: 0.442 AC: 1390 AN: 3144

South Asian (SAS) AF: 0.447 AC: 5442 AN: 12182

European-Finnish (FIN) AF: 0.159 AC: 72 AN: 452

Middle Eastern (MID) AF: 0.177 AC: 195 AN: 1100

European-Non Finnish (NFE) AF: 0.154 AC: 90218 AN: 586246

Other (OTH) AF: 0.233 AC: 4945 AN: 21212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.369 AC: 40540 AN: 109823 Hom.: 8763 Cov.: 11 AF XY: 0.354 AC XY: 11391 AN XY: 32193

African (AFR) AF: 0.804 AC: 24078 AN: 29950

American (AMR) AF: 0.366 AC: 3737 AN: 10213

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 407 AN: 2630

East Asian (EAS) AF: 0.437 AC: 1494 AN: 3417

South Asian (SAS) AF: 0.440 AC: 1130 AN: 2567

European-Finnish (FIN) AF: 0.152 AC: 885 AN: 5807

Middle Eastern (MID) AF: 0.199 AC: 42 AN: 211

European-Non Finnish (NFE) AF: 0.156 AC: 8222 AN: 52845

Other (OTH) AF: 0.319 AC: 481 AN: 1508

Alfa AF: 0.306 Hom.: 1886

Bravo AF: 0.414

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Deafness dystonia syndrome Benign:1

Feb 06, 2003

GeneReviews

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4024308; hg19: chrX-100600981; COSMIC: COSV58120356; COSMIC: COSV58120356;