19-39480590-C-T

Variant names:

• chr19-39480590-C-T
• rs1402361435
• ENST00000544017.5:c.46C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000544017.5(TIMM50):​c.46C>T​(p.Arg16Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TIMM50 ENST00000544017.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.35
• Publications: 3 publications found

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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06698713).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000544017.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM50	NM_001001563.5	MANE Select	c.-264C>T		upstream_gene	N/A	NP_001001563.2	Q3ZCQ8-1
	TIMM50	NM_001329559.2		c.-544C>T		upstream_gene	N/A	NP_001316488.1	Q3ZCQ8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM50	ENST00000544017.5	TSL:1	c.46C>T	p.Arg16Cys	missense	Exon 1 of 11	ENSP00000445806.2	Q3ZCQ8-2
	TIMM50	ENST00000601358.5	TSL:1	n.-264C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000472476.2	M0R2D2
	TIMM50	ENST00000601358.5	TSL:1	n.-264C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000472476.2	M0R2D2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152278 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74408

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.15
DANN	Benign	0.90
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.00094	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.98	T
PhyloP100		-2.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.031
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.21
MutPred		0.35		Gain of sheet (P = 0.0827)
MVP		0.085
MPC		0.53
ClinPred		0.16	T
GERP RS		-6.7
PromoterAI		-0.035	Neutral
gMVP		0.13
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1402361435; hg19: chr19-39971230; COSMIC: COSV100068003; COSMIC: COSV100068003;