Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001128917.2(TOMM40):c.147T>G(p.Ser49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,441,996 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S49G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 24 hom., cov: 33)

Exomes 𝑓: 0.015 ( 184 hom. )

Consequence

TOMM40
NM_001128917.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.00

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028074384).

BP6

Variant 19-44891562-T-G is Benign according to our data. Variant chr19-44891562-T-G is described in ClinVar as Benign. ClinVar VariationId is 774355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1814/152240) while in subpopulation NFE AF = 0.0178 (1209/67978). AF 95% confidence interval is 0.017. There are 24 homozygotes in GnomAd4. There are 904 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1814 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
TOMM40	NM_001128917.2	MANE Select	c.147T>G	p.Ser49Arg	missense	Exon 1 of 9	NP_001122389.1
TOMM40	NM_001128916.2		c.147T>G	p.Ser49Arg	missense	Exon 2 of 10	NP_001122388.1
TOMM40	NM_006114.3		c.147T>G	p.Ser49Arg	missense	Exon 2 of 10	NP_006105.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TOMM40	ENST00000426677.7	TSL:1 MANE Select	c.147T>G	p.Ser49Arg	missense	Exon 1 of 9	ENSP00000410339.1
TOMM40	ENST00000252487.9	TSL:1	c.147T>G	p.Ser49Arg	missense	Exon 2 of 10	ENSP00000252487.4
TOMM40	ENST00000405636.6	TSL:1	c.147T>G	p.Ser49Arg	missense	Exon 2 of 10	ENSP00000385184.2

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1814

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00536

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0314

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00984

AC:

696

AN:

70734

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00372

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0266

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0151

AC:

19458

AN:

1289756

Hom.:

184

Cov.:

AF XY:

0.0148

AC XY:

9383

AN XY:

634026

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

26280

American (AMR)

AF:

0.00443

AC:

109

AN:

24624

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

283

AN:

22358

East Asian (EAS)

AF:

0.00

AC:

AN:

27894

South Asian (SAS)

AF:

0.00273

AC:

191

AN:

70044

European-Finnish (FIN)

AF:

0.0276

AC:

902

AN:

32720

Middle Eastern (MID)

AF:

0.00398

AC:

AN:

3766

European-Non Finnish (NFE)

AF:

0.0168

AC:

17326

AN:

1029224

Other (OTH)

AF:

0.0111

AC:

584

AN:

52846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1095

2189

3284

4378

5473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.0119

AC:

1814

AN:

152240

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

904

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41550

American (AMR)

AF:

0.00536

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0314

AC:

333

AN:

10602

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0178

AC:

1209

AN:

67978

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

196

295

393

491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0110

Hom.:

Bravo

AF:

0.00941

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.000405

AC:

ESP6500EA

AF:

0.0119

AC:

ExAC

AF:

0.00276

AC:

182

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.9

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.079

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.35

REVEL

Benign

0.0090

Sift

Benign

0.49

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.067

MutPred

0.26

Loss of glycosylation at S49 (P = 0.006)

MVP

0.043

MPC

0.057

ClinPred

0.00086

GERP RS

-2.8

PromoterAI

0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

Mutation Taster

=100/0

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over