Variant 19-44894030-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001128917.2(TOMM40):c.607G>A(p.Val203Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,531,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

TOMM40
NM_001128917.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04430473).

BS2

High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMM40	NM_001128917.2 linkuse as main transcript	c.607G>A	p.Val203Ile	missense_variant	5/9	ENST00000426677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMM40	ENST00000426677.7 linkuse as main transcript	c.607G>A	p.Val203Ile	missense_variant	5/9	1	NM_001128917.2	P1	O96008-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

188644

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

99792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000834

AC:

115

AN:

1379226

Hom.:

Cov.:

AF XY:

0.0000872

AC XY:

AN XY:

676960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000865

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000515

Gnomad4 OTH exome

AF:

0.000211

GnomAD4 genome

AF:

0.000105

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000133

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The c.607G>A (p.V203I) alteration is located in exon 6 (coding exon 5) of the TOMM40 gene. This alteration results from a G to A substitution at nucleotide position 607, causing the valine (V) at amino acid position 203 to be replaced by an isoleucine (I). 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

0.068

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.069

T;T;.;T;T

Eigen

Benign

-0.053

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.55

T;.;T;.;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.044

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.090

N;N;.;N;.

REVEL

Benign

0.098

Sift

Benign

0.18

T;T;.;T;.

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.39

B;B;P;B;.

Vest4

0.28

MVP

0.24

MPC

0.92

ClinPred

0.11

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over