Genetic Variant TOMM40:p.Leu282Met (chr19-44901208-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001128917.2(TOMM40):c.844C>A(p.Leu282Met) variant causes a missense, splice region 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. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L282L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TOMM40
NM_001128917.2 missense, splice_region

Scores

Splicing: ADA: 0.00008148

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00100

Publications

0 publications found

Variant links:

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]

TOMM40 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4061705).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128917.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOMM40	NM_001128917.2	MANE Select	c.844C>A	p.Leu282Met	missense splice_region	Exon 8 of 9	NP_001122389.1	O96008-1
TOMM40	NM_001128916.2		c.844C>A	p.Leu282Met	missense splice_region	Exon 9 of 10	NP_001122388.1	O96008-1
TOMM40	NM_006114.3		c.844C>A	p.Leu282Met	missense splice_region	Exon 9 of 10	NP_006105.1	O96008-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOMM40	ENST00000426677.7	TSL:1 MANE Select	c.844C>A	p.Leu282Met	missense splice_region	Exon 8 of 9	ENSP00000410339.1	O96008-1
TOMM40	ENST00000252487.9	TSL:1	c.844C>A	p.Leu282Met	missense splice_region	Exon 9 of 10	ENSP00000252487.4	O96008-1
TOMM40	ENST00000405636.6	TSL:1	c.844C>A	p.Leu282Met	missense splice_region	Exon 9 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250602

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.85

M_CAP

Benign

0.035

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

3.2

PhyloP100

0.0010

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.85

REVEL

Benign

0.27

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.52

MutPred

0.76

Gain of ubiquitination at K277 (P = 0.0668)

MVP

0.51

MPC

2.1

ClinPred

0.82

GERP RS

0.018

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000081

dbscSNV1_RF

Benign

0.012

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