Variant chr1-161226555-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032174.6(TOMM40L):c.66A>T(p.Glu22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

TOMM40L
NM_032174.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0340

Variant links:

Genes affected

TOMM40L (HGNC:25756): (translocase of outer mitochondrial membrane 40 like) Predicted to enable protein transmembrane transporter activity. Predicted to be involved in protein import into mitochondrial matrix. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

TOMM40L links:

TOMM40L (HGNC:):

TOMM40L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03967613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMM40L	NM_032174.6 linkuse as main transcript	c.66A>T	p.Glu22Asp	missense_variant	2/10	ENST00000367988.8	NP_115550.2	Q969M1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM40L	ENST00000367988.8 linkuse as main transcript	c.66A>T	p.Glu22Asp	missense_variant	2/10	2	NM_032174.6	ENSP00000356967.3		Q969M1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251104

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.66A>T (p.E22D) alteration is located in exon 2 (coding exon 1) of the TOMM40L gene. This alteration results from a A to T substitution at nucleotide position 66, causing the glutamic acid (E) at amino acid position 22 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

.;T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.81

T;.;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.68

N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.29

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.61

T;T;T

Sift4G

Benign

0.72

T;T;T

Polyphen

0.0060

.;B;B

Vest4

0.11

MutPred

0.20

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.043

MPC

0.45

ClinPred

0.063

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over