chrX-101348670-G-A

Variant names:

• chrX-101348670-G-A
• rs180806413
• NM_004085.4:c.-6C>T

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM8A	NM_004085.4	c.-6C>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000372902.4	NP_004076.1
TIMM8A	NM_001145951.2	c.-6C>T		5_prime_UTR_variant	Exon 1 of 2		NP_001139423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM8A	ENST00000372902.4	c.-6C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_004085.4	ENSP00000361993.3

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 791 AN: 111573 Hom.: 5 Cov.: 22

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

GnomAD2 exomes AF: 0.00687 AC: 1257 AN: 183064 AF XY: 0.00694

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 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 AC: 35 AN: 26377

Gnomad4 AMR exome AF: 0.00290 AC: 102 AN: 35184

Gnomad4 ASJ exome AF: 0.000620 AC: 12 AN: 19367

Gnomad4 EAS exome AF: 0.0000331 AC: 1 AN: 30180

Gnomad4 SAS exome AF: 0.000813 AC: 44 AN: 54109

Gnomad4 FIN exome AF: 0.00594 AC: 240 AN: 40421

Gnomad4 NFE exome AF: 0.0132 AC: 11077 AN: 841790

Gnomad4 Remaining exome AF: 0.00917 AC: 422 AN: 46027

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 AC: 0.00168848 AN: 0.00168848

Gnomad4 AMR AF: 0.00474 AC: 0.00474473 AN: 0.00474473

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000376 AC: 0.000375516 AN: 0.000375516

Gnomad4 FIN AF: 0.00483 AC: 0.00483414 AN: 0.00483414

Gnomad4 NFE AF: 0.0121 AC: 0.0121399 AN: 0.0121399

Gnomad4 OTH AF: 0.00923 AC: 0.00922874 AN: 0.00922874

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

Mar 20, 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

-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 -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 02, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
Mutation Taster		=300/0	polymorphism (auto)

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;