Genetic Variant TOMM40:p.Ala65Thr (chr19-44891608-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001128917.2(TOMM40):c.193G>A(p.Ala65Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000756 in 1,323,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

TOMM40
NM_001128917.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.226

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04855886).

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.193G>A	p.Ala65Thr	missense	Exon 1 of 9	NP_001122389.1	O96008-1
TOMM40	NM_001128916.2		c.193G>A	p.Ala65Thr	missense	Exon 2 of 10	NP_001122388.1	O96008-1
TOMM40	NM_006114.3		c.193G>A	p.Ala65Thr	missense	Exon 2 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.193G>A	p.Ala65Thr	missense	Exon 1 of 9	ENSP00000410339.1	O96008-1
TOMM40	ENST00000252487.9	TSL:1	c.193G>A	p.Ala65Thr	missense	Exon 2 of 10	ENSP00000252487.4	O96008-1
TOMM40	ENST00000405636.6	TSL:1	c.193G>A	p.Ala65Thr	missense	Exon 2 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.56e-7

AC:

AN:

1323434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

652534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26866

American (AMR)

AF:

0.00

AC:

AN:

28288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23258

East Asian (EAS)

AF:

0.0000344

AC:

AN:

29054

South Asian (SAS)

AF:

0.00

AC:

AN:

74330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3870

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1049838

Other (OTH)

AF:

0.00

AC:

AN:

54646

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.43

M_CAP

Benign

0.0065

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.23

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.10

REVEL

Benign

0.011

Sift

Benign

0.093

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.047

MutPred

0.16

Gain of glycosylation at A65 (P = 0.0051)

MVP

0.10

MPC

0.051

ClinPred

0.061

GERP RS

1.7

PromoterAI

0.027

Neutral

(source)

Varity_R

0.022

Mutation Taster

=88/12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over