chr19-39482885-G-C

Position:

chr19-39482885-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The ENST00000607714.6(TIMM50):c.260G>C(p.Gly87Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TIMM50
ENST00000607714.6 missense, splice_region

Scores

Splicing: ADA: 0.9992

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a topological_domain Mitochondrial intermembrane (size 266) in uniprot entity TIM50_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in ENST00000607714.6

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-39482885-G-C is Pathogenic according to our data. Variant chr19-39482885-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 559479.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TIMM50	NM_001001563.5 linkuse as main transcript	c.260G>C	p.Gly87Ala	missense_variant, splice_region_variant	3/11	ENST00000607714.6	NP_001001563.2
TIMM50	XM_011527491.4 linkuse as main transcript	c.224G>C	p.Gly75Ala	missense_variant, splice_region_variant	3/11		XP_011525793.1
TIMM50	NM_001329559.2 linkuse as main transcript	c.-21G>C		splice_region_variant, 5_prime_UTR_variant	3/10		NP_001316488.1
TIMM50	XM_047439681.1 linkuse as main transcript	c.-113G>C		splice_region_variant, 5_prime_UTR_variant	3/11		XP_047295637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMM50	ENST00000607714.6 linkuse as main transcript	c.260G>C	p.Gly87Ala	missense_variant, splice_region_variant	3/11	1	NM_001001563.5	ENSP00000475531	P1	Q3ZCQ8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251484

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

3-methylglutaconic aciduria type 9

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2021

- -

Mitochondrial encephalopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control;in vitro

Zeviani Lab, University of Cambridge

The variants are reported in an Italian infant patient with rapidly progressive, severe encephalopathy. In vitro functional analysis on skin fibroblasts showed low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential and impaired TIM23-dependent protein import. As a consequence, steady-state levels of several components of mitochondrial respiratory chain were decreased, resulting in decreased respiration and increased ROS production. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0071

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.20

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.71

MutationTaster

Benign

1.0

D;D

Sift4G

Benign

0.26

MVP

0.60

ClinPred

0.99

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over