11-57528863-G-A

Variant names:

• chr11-57528863-G-A
• NM_012456.3:c.127C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012456.3(TIMM10):​c.127C>T​(p.Leu43Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TIMM10 NM_012456.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

Genes affected

TIMM10 (HGNC:11814): (translocase of inner mitochondrial membrane 10) The mitochondrial protein encoded by this gene belongs to a family of evolutionarily conserved proteins that are organized in heterooligomeric complexes in the mitochondrial intermembrane space. These proteins mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane, functioning as intermembrane space chaperones for the highly insoluble carrier proteins. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM10	NM_012456.3	c.127C>T	p.Leu43Phe	missense_variant	Exon 3 of 3	ENST00000257245.9	NP_036588.1
TIMM10	XM_024448436.2	c.127C>T	p.Leu43Phe	missense_variant	Exon 3 of 3		XP_024304204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM10	ENST00000257245.9	c.127C>T	p.Leu43Phe	missense_variant	Exon 3 of 3	1	NM_012456.3	ENSP00000257245.4
TIMM10	ENST00000525158.1	c.127C>T	p.Leu43Phe	missense_variant	Exon 3 of 3	2		ENSP00000433627.1
TIMM10	ENST00000525587.1	c.127C>T	p.Leu43Phe	missense_variant	Exon 3 of 3	3		ENSP00000435678.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127C>T (p.L43F) alteration is located in exon 3 (coding exon 2) of the TIMM10 gene. This alteration results from a C to T substitution at nucleotide position 127, causing the leucine (L) at amino acid position 43 to be replaced by a phenylalanine (F). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.58	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.83		Gain of catalytic residue at L43 (P = 0.0787);Gain of catalytic residue at L43 (P = 0.0787);Gain of catalytic residue at L43 (P = 0.0787);
MVP		0.97
MPC		1.4
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.94

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: chr11-57296336;