19-44892904-G-A

Variant names:

• chr19-44892904-G-A
• NM_001128917.2:c.410G>A

Variant summary

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

The NM_001128917.2(TOMM40):​c.410G>A​(p.Gly137Glu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.47

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 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, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM40	NM_001128917.2	c.410G>A	p.Gly137Glu	missense_variant	Exon 3 of 9	ENST00000426677.7	NP_001122389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM40	ENST00000426677.7	c.410G>A	p.Gly137Glu	missense_variant	Exon 3 of 9	1	NM_001128917.2	ENSP00000410339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.410G>A (p.G137E) alteration is located in exon 4 (coding exon 3) of the TOMM40 gene. This alteration results from a G to A substitution at nucleotide position 410, causing the glycine (G) at amino acid position 137 to be replaced by a glutamic acid (E). 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	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;.;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Pathogenic	3.4	M;M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D;D;.;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;.;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.97
MutPred		0.73		Gain of catalytic residue at G137 (P = 0.0169);Gain of catalytic residue at G137 (P = 0.0169);Gain of catalytic residue at G137 (P = 0.0169);Gain of catalytic residue at G137 (P = 0.0169);Gain of catalytic residue at G137 (P = 0.0169);
MVP		0.65
MPC		0.38
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95

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: chr19-45396161;