rs797044891

Variant names:

• chr19-39488169-G-A
• rs797044891
• NM_001001563.5:c.805G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001001563.5(TIMM50):​c.805G>A​(p.Gly269Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TIMM50 NM_001001563.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.23
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-39488169-G-A is Pathogenic according to our data. Variant chr19-39488169-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208697.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM50	NM_001001563.5	c.805G>A	p.Gly269Ser	missense_variant	Exon 9 of 11	ENST00000607714.6	NP_001001563.2
TIMM50	NM_001329559.2	c.466G>A	p.Gly156Ser	missense_variant	Exon 8 of 10		NP_001316488.1
TIMM50	XM_011527491.4	c.769G>A	p.Gly257Ser	missense_variant	Exon 9 of 11		XP_011525793.1
TIMM50	XM_047439681.1	c.433G>A	p.Gly145Ser	missense_variant	Exon 9 of 11		XP_047295637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM50	ENST00000607714.6	c.805G>A	p.Gly269Ser	missense_variant	Exon 9 of 11	1	NM_001001563.5	ENSP00000475531.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461652 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria type 9 Pathogenic:1

Jan 14, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Aug 12, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1114G>A (p.G372S) alteration is located in coding exon 9 of the TIMM50 gene. This alteration results from a G to A substitution at nucleotide position 1114, causing the glycine (G) at amino acid position 372 to be replaced by a serine (S). The alteration is not observed in population databases: Based on data from the NHLBI Exome Sequencing Project (ESP), the TIMM50 c.1114G>A alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project or ExAC and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). The altered amino acid is conserved throughout evolution: The p.G372 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain: The G372S alteration is located in the conserved C-terminal domain of the Tim50 protein that interacts with the N-terminal domain of the Tim23 protein in the inter membrane space and regulates mitochondrial protein import of presequence-containing polypeptides (Geissler 2002; Yamamoto 2002; Guo 2004). The alteration is predicted deleterious by in silico models: The G372S alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T;.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.6	D;.;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.068	T;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;T;D;D
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.84
MutPred		0.45		.;.;Loss of catalytic residue at G269 (P = 0.0047);.;.;.;
MVP		0.51
MPC		1.0
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.77
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs797044891; hg19: chr19-39978809;