ENST00000544017.5:c.15A>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The ENST00000544017.5(TIMM50):c.15A>C(p.Leu5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,601,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

TIMM50
ENST00000544017.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.318

Publications

0 publications found

Variant links:

Genes affected

TIMM50 (HGNC:23656): (translocase of inner mitochondrial membrane 50) This gene encodes a subunit of the TIM23 inner mitochondrial membrane translocase complex. The encoded protein functions as the receptor subunit that recognizes the mitochondrial targeting signal, or presequence, on protein cargo that is destined for the mitochondrial inner membrane and matrix. This protein may also play a role in maintaining the membrane permeability barrier, and knockdown of this gene in human cells results in the release of cytochrome c and apoptosis. [provided by RefSeq, Jul 2016]

TIMM50 Gene-Disease associations (from GenCC):

3-methylglutaconic aciduria type 9
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

TIMM50 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0112989545).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000642 (93/1449206) while in subpopulation MID AF = 0.00035 (2/5722). AF 95% confidence interval is 0.0000614. There are 0 homozygotes in GnomAdExome4. There are 46 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TIMM50	ENST00000544017.5 link	c.15A>C	p.Leu5Phe	missense_variant	Exon 1 of 11	1	ENSP00000445806.2	Q3ZCQ8-2
TIMM50	ENST00000601358.5 link	n.-295A>C		non_coding_transcript_exon_variant	Exon 1 of 10	1	ENSP00000472476.2	M0R2D2
TIMM50	ENST00000601358.5 link	n.-295A>C		5_prime_UTR_variant	Exon 1 of 10	1	ENSP00000472476.2	M0R2D2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000160

AC:

AN:

243872

AF XY:

0.000166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00154

Gnomad NFE exome

AF:

0.0000538

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000642

AC:

AN:

1449206

Hom.:

Cov.:

AF XY:

0.0000639

AC XY:

AN XY:

720064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32712

American (AMR)

AF:

0.00

AC:

AN:

41160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25664

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

85872

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000289

AC:

AN:

1105498

Other (OTH)

AF:

0.0000335

AC:

AN:

59770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000158

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000559

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 5 of the TIMM50 protein (p.Leu5Phe). This variant is present in population databases (rs778639102, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with TIMM50-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.29

CADD

Benign

3.2

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.43

.;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.32

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.060

N;.

REVEL

Benign

0.019

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0010

B;B

Vest4

0.13

MutPred

0.13

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.13

MPC

0.90

ClinPred

0.12

GERP RS

0.48

PromoterAI

0.091

Neutral

(source)

gMVP

0.036

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

ENST00000544017.5:c.15A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over