19-39480583-C-T

Variant names:

• chr19-39480583-C-T
• rs2146145287
• ENST00000544017.5:c.39C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The ENST00000544017.5(TIMM50):​c.39C>T​(p.Pro13Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,988 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TIMM50 ENST00000544017.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.03
• Publications: 0 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-39480583-C-T is Benign according to our data. Variant chr19-39480583-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1615565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.03 with no splicing effect.

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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM50	ENST00000544017.5	TSL:1	c.39C>T	p.Pro13Pro	synonymous	Exon 1 of 11	ENSP00000445806.2	Q3ZCQ8-2
	TIMM50	ENST00000601358.5	TSL:1	n.-271C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000472476.2	M0R2D2
	TIMM50	ENST00000601358.5	TSL:1	n.-271C>T		5_prime_UTR	Exon 1 of 10	ENSP00000472476.2	M0R2D2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460988 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726808

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111620

Other (OTH) AF: 0.0000331 AC: 2 AN: 60352

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.0
DANN	Benign	0.67
PhyloP100		-2.0
PromoterAI		-0.012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2146145287; hg19: chr19-39971223;