19-2427001-T-C

Variant names:

• chr19-2427001-T-C
• NM_012458.4:c.235A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012458.4(TIMM13):​c.235A>G​(p.Thr79Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TIMM13 NM_012458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

TIMM13 (HGNC:11816): (translocase of inner mitochondrial membrane 13) This gene encodes a member of the evolutionarily conserved TIMM (translocase of inner mitochondrial membrane) family of proteins that function as chaperones in the import of proteins from the cytoplasm into the mitochondrial inner membrane. Proteins of this family play a role in collecting substrate proteins from the translocase of the outer mitochondrial membrane (TOM) complex and delivering them to either the sorting and assembly machinery in the outer mitochondrial membrane (SAM) complex or the TIMM22 complex in the inner mitochondrial membrane. The encoded protein and the translocase of mitochondrial inner membrane 8a protein form a 70 kDa complex in the intermembrane space. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30019206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM13	NM_012458.4	c.235A>G	p.Thr79Ala	missense_variant	Exon 3 of 3	ENST00000215570.8	NP_036590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM13	ENST00000215570.8	c.235A>G	p.Thr79Ala	missense_variant	Exon 3 of 3	1	NM_012458.4	ENSP00000215570.2
TIMM13	ENST00000591871.1	c.190A>G	p.Thr64Ala	missense_variant	Exon 3 of 3	5		ENSP00000464881.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.235A>G (p.T79A) alteration is located in exon 3 (coding exon 3) of the TIMM13 gene. This alteration results from a A to G substitution at nucleotide position 235, causing the threonine (T) at amino acid position 79 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.062	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.014
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.059
Sift	Benign	0.45	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.016	B;.
Vest4		0.36
MutPred		0.30		Loss of phosphorylation at T79 (P = 0.0304);.;
MVP		0.53
MPC		0.30
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2426999;