19-39480570-A-C

Variant names:

• chr19-39480570-A-C
• rs778485461
• ENST00000544017.5:c.26A>C

Variant summary

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

The ENST00000544017.5(TIMM50):​c.26A>C​(p.Asn9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N9S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TIMM50 ENST00000544017.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

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=0.049924135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM50	ENST00000544017.5	c.26A>C	p.Asn9Thr	missense_variant	Exon 1 of 11	1		ENSP00000445806.2
TIMM50	ENST00000601358.5	n.-284A>C		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000472476.2
TIMM50	ENST00000601358.5	n.-284A>C		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000472476.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.19
DANN	Benign	0.96
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.82
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.030	N;.
REVEL	Benign	0.0090
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0020	B;B
Vest4		0.097
MutPred		0.12		Loss of stability (P = 0.0429);Loss of stability (P = 0.0429);
MVP		0.088
MPC		0.74
ClinPred		0.23	T
GERP RS		-3.1
PromoterAI		0.046	Neutral
gMVP		0.065
Mutation Taster		=98/2	polymorphism

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: rs778485461; hg19: chr19-39971210;