19-44891639-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001128917.2(TOMM40):c.224G>T(p.Gly75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000752 in 1,330,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

Genes affected

TOMM40 (HGNC:18001): (translocase of outer mitochondrial membrane 40) The protein encoded by this gene is localized in the outer membrane of the mitochondria. It is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for import of protein precursors into mitochondria. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06736398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMM40	NM_001128917.2	c.224G>T	p.Gly75Val	missense_variant	1/9	ENST00000426677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMM40	ENST00000426677.7	c.224G>T	p.Gly75Val	missense_variant	1/9	1	NM_001128917.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.52e-7 AC: 1 AN: 1330418 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 656482

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The c.224G>T (p.G75V) alteration is located in exon 2 (coding exon 1) of the TOMM40 gene. This alteration results from a G to T substitution at nucleotide position 224, causing the glycine (G) at amino acid position 75 to be replaced by a valine (V). 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	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.078	T;T;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.55	T;.;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.86	N;N;.;N;.
REVEL	Benign	0.021
Sift	Benign	0.14	T;T;.;T;.
Sift4G	Benign	0.080	T;T;T;T;T
Polyphen		0.22	B;B;P;B;.
Vest4		0.11
MutPred		0.32		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.068
MPC		0.36
ClinPred		0.11	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065

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

LitVar

Other links and lift over

dbSNP: rs1208903823; hg19: chr19-45394896;