19-39480879-C-T

Variant names:

• chr19-39480879-C-T
• rs35135520
• NM_001001563.5:c.26C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001329559.2(TIMM50):​c.-255C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,599,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIMM50 NM_001329559.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.204
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070655346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329559.2. 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.26C>T	p.Ser9Leu	missense	Exon 1 of 11	NP_001001563.2	Q3ZCQ8-1
	TIMM50	NM_001329559.2		c.-255C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001316488.1	Q3ZCQ8-3
	TIMM50	NM_001329559.2		c.-255C>T		5_prime_UTR	Exon 1 of 10	NP_001316488.1	Q3ZCQ8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM50	ENST00000607714.6	TSL:1 MANE Select	c.26C>T	p.Ser9Leu	missense	Exon 1 of 11	ENSP00000475531.1	Q3ZCQ8-1
	TIMM50	ENST00000544017.5	TSL:1	c.335C>T	p.Ser112Leu	missense	Exon 1 of 11	ENSP00000445806.2	Q3ZCQ8-2
	TIMM50	ENST00000601358.5	TSL:1	n.26C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000472476.2	M0R2D2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152268 Hom.: 0 Cov.: 34

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000457 AC: 1 AN: 218814 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447254 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719534

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 43528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 85134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108068

Other (OTH) AF: 0.00 AC: 0 AN: 59832

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152268 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74392

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000839 AC: 1

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	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.20
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.021
Sift	Benign	0.33	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.056
MutPred		0.26		Loss of phosphorylation at S112 (P = 0.021)
MVP		0.088
MPC		0.29
ClinPred		0.042	T
GERP RS		2.0
PromoterAI		0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.053
gMVP		0.21
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs35135520; hg19: chr19-39971519;