chr19-39482885-G-T

Position:

• chr19-39482885-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000607714.6(TIMM50):​c.260G>T​(p.Gly87Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G87A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TIMM50 ENST00000607714.6 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.43

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMM50	NM_001001563.5	c.260G>T	p.Gly87Val	missense_variant, splice_region_variant	3/11	ENST00000607714.6	NP_001001563.2
TIMM50	XM_011527491.4	c.224G>T	p.Gly75Val	missense_variant, splice_region_variant	3/11		XP_011525793.1
TIMM50	NM_001329559.2	c.-21G>T		splice_region_variant, 5_prime_UTR_variant	3/10		NP_001316488.1
TIMM50	XM_047439681.1	c.-113G>T		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	c.260G>T	p.Gly87Val	missense_variant, splice_region_variant	3/11	1	NM_001001563.5	ENSP00000475531	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MutationTaster	Benign	1.0	D;D
ClinPred		0.99	D
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	1.0
SpliceAI score (max)		0.060		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: rs776019250; hg19: chr19-39973525;