Genetic Variant TOMM20L:p.Lys129Asn (chr14-58407450-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207377.3(TOMM20L):c.387A>T(p.Lys129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TOMM20L
NM_207377.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00

Variant links:

Genes affected

TOMM20L (HGNC:33752): (translocase of outer mitochondrial membrane 20 like) Predicted to enable mitochondrion targeting sequence binding activity. Predicted to contribute to protein transmembrane transporter activity. Predicted to be involved in protein import into mitochondrial matrix and tRNA import into mitochondrion. Predicted to be integral component of membrane. Predicted to be part of mitochondrial outer membrane translocase complex. Predicted to be integral component of mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

TOMM20L links:

ENSG00000258378 (HGNC:):

ENSG00000258378 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24363753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM20L	NM_207377.3 link	c.387A>T	p.Lys129Asn	missense_variant	Exon 4 of 5	ENST00000360945.7	NP_997260.1	Q6UXN7
TOMM20L	XM_011536742.4 link	c.411A>T	p.Lys137Asn	missense_variant	Exon 4 of 5		XP_011535044.1
TOMM20L	XM_011536743.3 link	c.411A>T	p.Lys137Asn	missense_variant	Exon 4 of 5		XP_011535045.1
TOMM20L	XM_011536744.4 link	c.261A>T	p.Lys87Asn	missense_variant	Exon 2 of 3		XP_011535046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TOMM20L	ENST00000360945.7 link	c.387A>T	p.Lys129Asn	missense_variant	Exon 4 of 5	1	NM_207377.3	ENSP00000354204.2	Q6UXN7
TOMM20L	ENST00000557754.1 link	n.*80A>T		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000451683.1	G3V4A4
TOMM20L	ENST00000557754.1 link	n.*80A>T		3_prime_UTR_variant	Exon 3 of 4	1		ENSP00000451683.1	G3V4A4
ENSG00000258378	ENST00000556734.1 link	n.374+8520A>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726268

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

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

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.387A>T (p.K129N) alteration is located in exon 4 (coding exon 4) of the TOMM20L gene. This alteration results from a A to T substitution at nucleotide position 387, causing the lysine (K) at amino acid position 129 to be replaced by an asparagine (N). 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

0.30

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

0.076

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.54

M_CAP

Benign

0.0088

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.17

Sift

Benign

0.031

Sift4G

Uncertain

0.029

Polyphen

0.61

Vest4

0.24

MutPred

0.57

Loss of ubiquitination at K129 (P = 0.0148);

MVP

0.30

MPC

1.1

ClinPred

0.95

GERP RS

3.8

Varity_R

0.35

gMVP

0.35

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over