Genetic Variant TOMM40:p.Ser43Asn (chr19-44891543-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.128G>A(p.Ser43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 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. S43T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TOMM40
NM_001128917.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50

Publications

1 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=0.06630337).

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.128G>A	p.Ser43Asn	missense	Exon 1 of 9	NP_001122389.1	O96008-1
TOMM40	NM_001128916.2		c.128G>A	p.Ser43Asn	missense	Exon 2 of 10	NP_001122388.1	O96008-1
TOMM40	NM_006114.3		c.128G>A	p.Ser43Asn	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.128G>A	p.Ser43Asn	missense	Exon 1 of 9	ENSP00000410339.1	O96008-1
TOMM40	ENST00000252487.9	TSL:1	c.128G>A	p.Ser43Asn	missense	Exon 2 of 10	ENSP00000252487.4	O96008-1
TOMM40	ENST00000405636.6	TSL:1	c.128G>A	p.Ser43Asn	missense	Exon 2 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1267560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

621676

African (AFR)

AF:

0.00

AC:

AN:

26032

American (AMR)

AF:

0.00

AC:

AN:

22782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21806

East Asian (EAS)

AF:

0.00

AC:

AN:

27524

South Asian (SAS)

AF:

0.00

AC:

AN:

66058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1016010

Other (OTH)

AF:

0.00

AC:

AN:

51716

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.064

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.48

M_CAP

Benign

0.0097

MetaRNN

Benign

0.066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

1.5

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.17

REVEL

Benign

0.060

Sift

Benign

1.0

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.077

MutPred

0.19

Loss of glycosylation at S43 (P = 0.0055)

MVP

0.093

MPC

1.8

ClinPred

0.052

GERP RS

3.4

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

Mutation Taster

=94/6

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over