Genetic Variant TOMM40:c.946+124A>G (chr19-44901434-A-G) – 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.946+124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 1,494,492 control chromosomes in the GnomAD database, including 397,046 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 0.76 ( 45120 hom., cov: 34)

Exomes 𝑓: 0.72 ( 351926 hom. )

Consequence

TOMM40
NM_001128917.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.31

Publications

48 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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM40	NM_001128917.2 link	c.946+124A>G		intron_variant	Intron 8 of 8	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.946+124A>G		intron_variant	Intron 8 of 8	1	NM_001128917.2	ENSP00000410339.1		O96008-1

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116208

AN:

152096

Hom.:

45058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.876

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.811

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.648

Gnomad FIN

AF:

0.788

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.731

Gnomad OTH

AF:

0.755

GnomAD4 exome

AF:

0.721

AC:

968433

AN:

1342278

Hom.:

351926

Cov.:

AF XY:

0.720

AC XY:

471340

AN XY:

654762

show subpopulations

African (AFR)

AF:

0.882

AC:

26668

AN:

30234

American (AMR)

AF:

0.741

AC:

22035

AN:

29718

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

17318

AN:

21484

East Asian (EAS)

AF:

0.448

AC:

15745

AN:

35144

South Asian (SAS)

AF:

0.654

AC:

46546

AN:

71182

European-Finnish (FIN)

AF:

0.785

AC:

35646

AN:

45382

Middle Eastern (MID)

AF:

0.773

AC:

4167

AN:

5394

European-Non Finnish (NFE)

AF:

0.726

AC:

761012

AN:

1048312

Other (OTH)

AF:

0.709

AC:

39296

AN:

55428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

14410

28820

43229

57639

72049

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19588

39176

58764

78352

97940

<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:

0.764

AC:

116336

AN:

152214

Hom.:

45120

Cov.:

AF XY:

0.764

AC XY:

56850

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.876

AC:

36409

AN:

41554

American (AMR)

AF:

0.728

AC:

11134

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.811

AC:

2816

AN:

3472

East Asian (EAS)

AF:

0.429

AC:

2214

AN:

5166

South Asian (SAS)

AF:

0.649

AC:

3129

AN:

4818

European-Finnish (FIN)

AF:

0.788

AC:

8357

AN:

10604

Middle Eastern (MID)

AF:

0.779

AC:

229

AN:

294

European-Non Finnish (NFE)

AF:

0.731

AC:

49727

AN:

68000

Other (OTH)

AF:

0.757

AC:

1598

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1413

2827

4240

5654

7067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.749

Hom.:

42886

Bravo

AF:

0.763

Asia WGS

AF:

0.624

AC:

2170

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

(source)

DANN

Benign

0.21

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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