Genetic Variant TOMM40:c.435+33C>T (chr19-44892962-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001128917.2(TOMM40):c.435+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,560,052 control chromosomes in the GnomAD database, including 43,042 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 0.29 ( 7124 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35918 hom. )

Consequence

TOMM40
NM_001128917.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0150

Publications

123 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM40	NM_001128917.2 link	c.435+33C>T		intron_variant	Intron 3 of 8	ENST00000426677.7	NP_001122389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM40	ENST00000426677.7 link	c.435+33C>T		intron_variant	Intron 3 of 8	1	NM_001128917.2	ENSP00000410339.1

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43266

AN:

151914

Hom.:

7092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.153

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.209

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.239

GnomAD2 exomes

AF:

0.240

AC:

54992

AN:

229254

AF XY:

0.230

show subpopulations

Gnomad AFR exome

AF:

0.470

Gnomad AMR exome

AF:

0.286

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.236

Gnomad NFE exome

AF:

0.221

Gnomad OTH exome

AF:

0.218

GnomAD4 exome

AF:

0.222

AC:

312343

AN:

1408020

Hom.:

35918

Cov.:

AF XY:

0.219

AC XY:

153778

AN XY:

700788

show subpopulations

African (AFR)

AF:

0.475

AC:

15323

AN:

32260

American (AMR)

AF:

0.279

AC:

11722

AN:

42044

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

5075

AN:

25040

East Asian (EAS)

AF:

0.222

AC:

8719

AN:

39210

South Asian (SAS)

AF:

0.183

AC:

15209

AN:

83242

European-Finnish (FIN)

AF:

0.231

AC:

12177

AN:

52664

Middle Eastern (MID)

AF:

0.159

AC:

893

AN:

5634

European-Non Finnish (NFE)

AF:

0.215

AC:

230314

AN:

1069422

Other (OTH)

AF:

0.221

AC:

12911

AN:

58504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

10932

21864

32796

43728

54660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7962

15924

23886

31848

39810

<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:

0.285

AC:

43360

AN:

152032

Hom.:

7124

Cov.:

AF XY:

0.286

AC XY:

21282

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.461

AC:

19118

AN:

41442

American (AMR)

AF:

0.264

AC:

4025

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

681

AN:

3470

East Asian (EAS)

AF:

0.209

AC:

1079

AN:

5164

South Asian (SAS)

AF:

0.195

AC:

938

AN:

4800

European-Finnish (FIN)

AF:

0.224

AC:

2374

AN:

10578

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.212

AC:

14442

AN:

67986

Other (OTH)

AF:

0.245

AC:

518

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1472

2943

4415

5886

7358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.235

Hom.:

19283

Bravo

AF:

0.295

Asia WGS

AF:

0.318

AC:

1106

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.4

(source)

DANN

Benign

0.72

PhyloP100

0.015

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