19-39480879-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001329559.2(TIMM50):​c.-255C>G 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 0.00236 in 1,599,632 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (35 hom.)
• Consequence: TIMM50 NM_001329559.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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: 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

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>G	p.Ser9Trp	missense	Exon 1 of 11	NP_001001563.2	Q3ZCQ8-1
	TIMM50	NM_001329559.2		c.-255C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001316488.1	Q3ZCQ8-3
	TIMM50	NM_001329559.2		c.-255C>G		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>G	p.Ser9Trp	missense	Exon 1 of 11	ENSP00000475531.1	Q3ZCQ8-1
	TIMM50	ENST00000544017.5	TSL:1	c.335C>G	p.Ser112Trp	missense	Exon 1 of 11	ENSP00000445806.2	Q3ZCQ8-2
	TIMM50	ENST00000601358.5	TSL:1	n.26C>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000472476.2	M0R2D2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1940 AN: 152264 Hom.: 44 Cov.: 34

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

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.: 35 Cov.: 32 AF XY: 0.00106 AC XY: 766 AN XY: 719532

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: 0 AN: 25838

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39310

South Asian (SAS) AF: 0.0000705 AC: 6 AN: 85134

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

Middle Eastern (MID) AF: 0.00143 AC: 8 AN: 5588

European-Non Finnish (NFE) AF: 0.0000614 AC: 68 AN: 1108066

Other (OTH) AF: 0.00328 AC: 196 AN: 59832

GnomAD4 genome AF: 0.0128 AC: 1943 AN: 152382 Hom.: 44 Cov.: 34 AF XY: 0.0119 AC XY: 886 AN XY: 74516

African (AFR) AF: 0.0441 AC: 1833 AN: 41592

American (AMR) AF: 0.00562 AC: 86 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.0142

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0345 AC: 146

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00377 AC: 449

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	3-methylglutaconic aciduria type 9 (1)
-	-	1	TIMM50-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.065	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.20
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.067
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.039	D
Polyphen		0.98	D
Vest4		0.23
MVP		0.26
MPC		0.97
ClinPred		0.046	T
GERP RS		2.0
PromoterAI		-0.065	Neutral
Varity_R		0.057
gMVP		0.45
Mutation Taster		=95/5	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;