rs180806413

chrX-101348670-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004085.4(TIMM8A):c.-6C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,208,756 control chromosomes in the GnomAD database, including 53 homozygotes. There are 3,990 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (5 hom., 215 hem., cov: 22)
  • Exomes 𝑓: 0.011 (48 hom. 3775 hem.)
• Consequence: TIMM8A NM_004085.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.479

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-101348670-G-A is Benign according to our data. Variant chrX-101348670-G-A is described in ClinVar as [Benign]. Clinvar id is 137659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101348670-G-A is described in Lovd as [Benign]. Variant chrX-101348670-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM8A	NM_004085.4	c.-6C>T		5_prime_UTR_variant	1/2	ENST00000372902.4
TIMM8A	NM_001145951.2	c.-6C>T		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMM8A	ENST00000372902.4	c.-6C>T		5_prime_UTR_variant	1/2	1	NM_004085.4	P1
TIMM8A	ENST00000644112.2	c.-6C>T		5_prime_UTR_variant	1/2
TIMM8A	ENST00000645279.1	c.-6C>T		5_prime_UTR_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 791 AN: 111573 Hom.: 5 Cov.: 22 AF XY: 0.00636 AC XY: 215 AN XY: 33783

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00475

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00483

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00935

GnomAD3 exomes AF: 0.00687 AC: 1257 AN: 183064 Hom.: 2 AF XY: 0.00694 AC XY: 469 AN XY: 67592

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.000267

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000786

Gnomad FIN exome AF: 0.00660

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00839

GnomAD4 exome AF: 0.0109 AC: 11936 AN: 1097125 Hom.: 48 Cov.: 33 AF XY: 0.0104 AC XY: 3775 AN XY: 362707

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.00290

Gnomad4 ASJ exome AF: 0.000620

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000813

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.00917

GnomAD4 genome AF: 0.00709 AC: 791 AN: 111631 Hom.: 5 Cov.: 22 AF XY: 0.00635 AC XY: 215 AN XY: 33851

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00474

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000376

Gnomad4 FIN AF: 0.00483

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00923

Alfa AF: 0.0103 Hom.: 83

Bravo AF: 0.00654

EpiCase AF: 0.0109

EpiControl AF: 0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	-6C>T in Exon 01 of TIMM8A: This variant is not expected to have clinical signif icance because it has been identified in 1.0% (58/5545) of European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washingto -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	12
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs180806413; hg19: chrX-100603658;