Genetic Variant NM_001128917.2:c.393C>T (chr19-44892887-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001128917.2(TOMM40):c.393C>T(p.Phe131Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,380 control chromosomes in the GnomAD database, including 15,939 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 1265 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14674 hom. )

Consequence

TOMM40
NM_001128917.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.945

Publications

88 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP7

Synonymous conserved (PhyloP=-0.945 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM40	NM_001128917.2 link	c.393C>T	p.Phe131Phe	synonymous_variant	Exon 3 of 9	ENST00000426677.7	NP_001122389.1	O96008-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM40	ENST00000426677.7 link	c.393C>T	p.Phe131Phe	synonymous_variant	Exon 3 of 9	1	NM_001128917.2	ENSP00000410339.1		O96008-1

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19320

AN:

152064

Hom.:

1257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.144

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.0933

GnomAD2 exomes

AF:

0.128

AC:

32087

AN:

250946

AF XY:

0.128

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.0972

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.0866

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.140

AC:

205087

AN:

1461198

Hom.:

14674

Cov.:

AF XY:

0.140

AC XY:

101775

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.107

AC:

3565

AN:

33464

American (AMR)

AF:

0.0974

AC:

4351

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2898

AN:

26132

East Asian (EAS)

AF:

0.129

AC:

5117

AN:

39696

South Asian (SAS)

AF:

0.118

AC:

10210

AN:

86228

European-Finnish (FIN)

AF:

0.175

AC:

9350

AN:

53410

Middle Eastern (MID)

AF:

0.0573

AC:

330

AN:

5760

European-Non Finnish (NFE)

AF:

0.146

AC:

161778

AN:

1111446

Other (OTH)

AF:

0.124

AC:

7488

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

8887

17774

26661

35548

44435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5712

11424

17136

22848

28560

<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:

0.127

AC:

19362

AN:

152182

Hom.:

1265

Cov.:

AF XY:

0.129

AC XY:

9591

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.112

AC:

4647

AN:

41532

American (AMR)

AF:

0.104

AC:

1591

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

398

AN:

3472

East Asian (EAS)

AF:

0.108

AC:

558

AN:

5170

South Asian (SAS)

AF:

0.122

AC:

589

AN:

4828

European-Finnish (FIN)

AF:

0.172

AC:

1823

AN:

10582

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9397

AN:

67988

Other (OTH)

AF:

0.0990

AC:

209

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

861

1722

2584

3445

4306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.113

Hom.:

839

Bravo

AF:

0.119

Asia WGS

AF:

0.171

AC:

596

AN:

3478

EpiCase

AF:

0.129

EpiControl

AF:

0.124

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

7.9

(source)

DANN

Benign

0.81

PhyloP100

-0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over