rs41309506

Variant names:

• chrX-101348375-T-C
• rs41309506
• NM_004085.4:c.132+158A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145951.2(TIMM8A):​c.*12A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,172,658 control chromosomes in the GnomAD database, including 160 homozygotes. There are 6,494 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., 401 hem., cov: 21)
  • Exomes 𝑓: 0.018 (149 hom. 6093 hem.)
• Consequence: TIMM8A NM_001145951.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.327

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-101348375-T-C is Benign according to our data. Variant chrX-101348375-T-C is described in ClinVar as [Benign]. Clinvar id is 44082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1348/110006) while in subpopulation NFE AF= 0.0177 (929/52607). AF 95% confidence interval is 0.0167. There are 11 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.132+158A>G		intron_variant	Intron 1 of 1	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.*12A>G		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.132+158A>G		intron_variant	Intron 1 of 1	1	NM_004085.4	ENSP00000361993.3

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1348 AN: 109950 Hom.: 11 Cov.: 21 AF XY: 0.0124 AC XY: 400 AN XY: 32276

Gnomad AFR AF: 0.00206

Gnomad AMI AF: 0.0613

Gnomad AMR AF: 0.00938

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00605

GnomAD3 exomes AF: 0.0136 AC: 1669 AN: 122550 Hom.: 15 AF XY: 0.0134 AC XY: 550 AN XY: 41086

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0175 AC: 18633 AN: 1062652 Hom.: 149 Cov.: 31 AF XY: 0.0176 AC XY: 6093 AN XY: 347068

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00619

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.0000717

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0123 AC: 1348 AN: 110006 Hom.: 11 Cov.: 21 AF XY: 0.0124 AC XY: 401 AN XY: 32342

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00936

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000577

Gnomad4 SAS AF: 0.0103

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.00597

Alfa AF: 0.0145 Hom.: 115

Bravo AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 03, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

*12A>G in Exon 02 of TIMM8A: This variant is not expected to have clinical signi ficance because it has been identified in 1.6% (30/1899) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs41309506). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs41309506; hg19: chrX-100603363;