Genetic Variant TIMM50:p.Arg32Ser (chr19-39480638-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000544017.5(TIMM50):c.94C>A(p.Arg32Ser) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TIMM50
ENST00000544017.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.346

Publications

0 publications found

Variant links:

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

TIMM50 links:

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ACMG classification

Classification was made for transcript

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=0.061625153).

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
	TIMM50	NM_001001563.5	MANE Select	c.-216C>A		upstream_gene	N/A	NP_001001563.2	Q3ZCQ8-1
	TIMM50	NM_001329559.2		c.-496C>A		upstream_gene	N/A	NP_001316488.1	Q3ZCQ8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMM50	ENST00000544017.5	TSL:1	c.94C>A	p.Arg32Ser	missense	Exon 1 of 11	ENSP00000445806.2	Q3ZCQ8-2
TIMM50	ENST00000601358.5	TSL:1	n.-216C>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000472476.2	M0R2D2
TIMM50	ENST00000601358.5	TSL:1	n.-216C>A		5_prime_UTR	Exon 1 of 10	ENSP00000472476.2	M0R2D2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.2

(source)

DANN

Uncertain

0.97

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.34

M_CAP

Benign

0.0062

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

PhyloP100

0.35

PrimateAI

Benign

0.34

PROVEAN

Benign

0.030

REVEL

Benign

0.043

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.041

Vest4

0.11

MutPred

0.095

Gain of phosphorylation at R32 (P = 0.0056)

MVP

0.092

MPC

0.75

ClinPred

0.99

GERP RS

2.3

PromoterAI

0.054

Neutral

(source)

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over