Genetic Variant TOMM40:p.Val210Ile (chr19-44894051-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001128917.2(TOMM40):c.628G>A(p.Val210Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000726 in 1,515,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

TOMM40
NM_001128917.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048139006).

BS2

High AC in GnomAd4 at 20 AD gene.

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.628G>A	p.Val210Ile	missense	Exon 5 of 9	NP_001122389.1	O96008-1
TOMM40	NM_001128916.2		c.628G>A	p.Val210Ile	missense	Exon 6 of 10	NP_001122388.1	O96008-1
TOMM40	NM_006114.3		c.628G>A	p.Val210Ile	missense	Exon 6 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.628G>A	p.Val210Ile	missense	Exon 5 of 9	ENSP00000410339.1	O96008-1
TOMM40	ENST00000252487.9	TSL:1	c.628G>A	p.Val210Ile	missense	Exon 6 of 10	ENSP00000252487.4	O96008-1
TOMM40	ENST00000405636.6	TSL:1	c.628G>A	p.Val210Ile	missense	Exon 6 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000799

AC:

AN:

175232

AF XY:

0.0000648

show subpopulations

Gnomad AFR exome

AF:

0.000272

Gnomad AMR exome

AF:

0.0000478

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000675

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000235

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000660

AC:

AN:

1363180

Hom.:

Cov.:

AF XY:

0.0000824

AC XY:

AN XY:

667590

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

30216

American (AMR)

AF:

0.0000323

AC:

AN:

30936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20184

East Asian (EAS)

AF:

0.0000795

AC:

AN:

37734

South Asian (SAS)

AF:

0.000394

AC:

AN:

71124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50062

Middle Eastern (MID)

AF:

0.000227

AC:

AN:

4406

European-Non Finnish (NFE)

AF:

0.0000367

AC:

AN:

1062550

Other (OTH)

AF:

0.0000357

AC:

AN:

55968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000731

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000931

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.047

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.70

M_CAP

Benign

0.0037

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

1.9

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.42

REVEL

Benign

0.047

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.046

Vest4

0.21

MVP

0.16

MPC

0.82

ClinPred

0.021

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over