Genetic Variant NM_207377.3:c.100C>G (chr14-58396057-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_207377.3(TOMM20L):c.100C>G(p.Arg34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000555 in 1,261,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TOMM20L
NM_207377.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.137

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM20L	NM_207377.3 link	c.100C>G	p.Arg34Gly	missense_variant	Exon 1 of 5	ENST00000360945.7	NP_997260.1	Q6UXN7
TOMM20L	XM_011536742.4 link	c.100C>G	p.Arg34Gly	missense_variant	Exon 1 of 5		XP_011535044.1
TOMM20L	XM_011536743.3 link	c.100C>G	p.Arg34Gly	missense_variant	Exon 1 of 5		XP_011535045.1
TOMM20L	XM_011536744.4 link	c.100C>G	p.Arg34Gly	missense_variant	Exon 1 of 3		XP_011535046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM20L	ENST00000360945.7 link	c.100C>G	p.Arg34Gly	missense_variant	Exon 1 of 5	1	NM_207377.3	ENSP00000354204.2		Q6UXN7
TOMM20L	ENST00000557754.1 link	n.100C>G		non_coding_transcript_exon_variant	Exon 1 of 4	1		ENSP00000451683.1		G3V4A4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

143894

Hom.:

AF XY:

0.0000479

AC XY:

AN XY:

83476

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:

0.000162

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000357

GnomAD4 exome

AF:

0.00000555

AC:

AN:

1261560

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

620894

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:

0.0000967

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000399

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000174

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100C>G (p.R34G) alteration is located in exon 1 (coding exon 1) of the TOMM20L gene. This alteration results from a C to G substitution at nucleotide position 100, causing the arginine (R) at amino acid position 34 to be replaced by a glycine (G). 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

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.79

MutationAssessor

Pathogenic

3.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Benign

0.14

Polyphen

0.98

Vest4

0.47

MutPred

0.66

Loss of solvent accessibility (P = 0.0159);

MVP

0.35

MPC

1.6

ClinPred

0.58

GERP RS

2.7

Varity_R

0.82

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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