X-101346567-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004085.4(TIMM8A):c.226T>C(p.Phe76Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F76V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TIMM8A NM_004085.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM8A	NM_004085.4	c.226T>C	p.Phe76Leu	missense_variant	2/2	ENST00000372902.4
TIMM8A	NM_001145951.2	c.*1820T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMM8A	ENST00000372902.4	c.226T>C	p.Phe76Leu	missense_variant	2/2	1	NM_004085.4	P1
TIMM8A	ENST00000644112.2	c.*1820T>C		3_prime_UTR_variant	2/2
TIMM8A	ENST00000647480.1	n.743T>C		non_coding_transcript_exon_variant	2/2
TIMM8A	ENST00000645279.1	c.*420T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 76 of the TIMM8A protein (p.Phe76Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TIMM8A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
Polyphen		0.73	P;P
Vest4		0.76
MutPred		0.46		Gain of disorder (P = 0.1571);Gain of disorder (P = 0.1571);
MVP		0.88
MPC		1.5
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100601555;