19-39480879-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001001563.5(TIMM50):c.26C>G(p.Ser9Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,599,632 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S9L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 44 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 35 hom. )

Consequence

TIMM50
NM_001001563.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.204

Publications

5 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029362142).

BP6

Variant 19-39480879-C-G is Benign according to our data. Variant chr19-39480879-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 780558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1943/152382) while in subpopulation AFR AF = 0.0441 (1833/41592). AF 95% confidence interval is 0.0424. There are 44 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TIMM50	NM_001001563.5 link	c.26C>G	p.Ser9Trp	missense_variant	Exon 1 of 11	ENST00000607714.6	NP_001001563.2
TIMM50	NM_001329559.2 link	c.-255C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		NP_001316488.1
TIMM50	NM_001329559.2 link	c.-255C>G		5_prime_UTR_variant	Exon 1 of 10		NP_001316488.1
TIMM50	XM_011527491.4 link	c.-110C>G		upstream_gene_variant			XP_011525793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM50	ENST00000607714.6 link	c.26C>G	p.Ser9Trp	missense_variant	Exon 1 of 11	1	NM_001001563.5	ENSP00000475531.1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1940

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00562

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00312

AC:

682

AN:

218814

AF XY:

0.00226

show subpopulations

Gnomad AFR exome

AF:

0.0444

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000815

Gnomad OTH exome

AF:

0.00128

GnomAD4 exome

AF:

0.00126

AC:

1830

AN:

1447250

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

766

AN XY:

719532

show subpopulations

African (AFR)

AF:

0.0419

AC:

1394

AN:

33298

American (AMR)

AF:

0.00354

AC:

154

AN:

43528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25838

East Asian (EAS)

AF:

0.000102

AC:

AN:

39310

South Asian (SAS)

AF:

0.0000705

AC:

AN:

85134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46656

Middle Eastern (MID)

AF:

0.00143

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.0000614

AC:

AN:

1108066

Other (OTH)

AF:

0.00328

AC:

196

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

127

254

381

508

635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0128

AC:

1943

AN:

152382

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

886

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0441

AC:

1833

AN:

41592

American (AMR)

AF:

0.00562

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68040

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000731

Hom.:

Bravo

AF:

0.0142

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0345

AC:

146

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00377

AC:

449

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

3-methylglutaconic aciduria type 9

Benign:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TIMM50-related disorder

Benign:1

Oct 07, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.035

.;.;T;.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.065

LIST_S2

Uncertain

0.91

.;D;D;D;D;D

MetaRNN

Benign

0.0029

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;.;L;.;.;.

PhyloP100

0.20

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;.;.;.;.;.

REVEL

Benign

0.067

Sift

Uncertain

0.0060

D;.;.;.;.;.

Sift4G

Uncertain

0.039

D;D;T;D;D;T

Polyphen

0.98

D;D;.;.;.;.

Vest4

0.23

MVP

0.26

MPC

0.97

ClinPred

0.046

GERP RS

2.0

PromoterAI

-0.065

Neutral

(source)

Varity_R

0.057

gMVP

0.45

Mutation Taster

=95/5

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

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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