chr14-58407376-G-A

Variant names:

• chr14-58407376-G-A
• rs141434824
• NM_207377.3:c.313G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207377.3(TOMM20L):​c.313G>A​(p.Glu105Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: TOMM20L NM_207377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.808

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]

ENSG00000258378 (HGNC:):

ACMG classification

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=0.016920984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM20L	NM_207377.3	c.313G>A	p.Glu105Lys	missense_variant	Exon 4 of 5	ENST00000360945.7	NP_997260.1
TOMM20L	XM_011536742.4	c.337G>A	p.Glu113Lys	missense_variant	Exon 4 of 5		XP_011535044.1
TOMM20L	XM_011536743.3	c.337G>A	p.Glu113Lys	missense_variant	Exon 4 of 5		XP_011535045.1
TOMM20L	XM_011536744.4	c.187G>A	p.Glu63Lys	missense_variant	Exon 2 of 3		XP_011535046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM20L	ENST00000360945.7	c.313G>A	p.Glu105Lys	missense_variant	Exon 4 of 5	1	NM_207377.3	ENSP00000354204.2
TOMM20L	ENST00000557754.1	n.*6G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000451683.1
TOMM20L	ENST00000557754.1	n.*6G>A		3_prime_UTR_variant	Exon 3 of 4	1		ENSP00000451683.1
ENSG00000258378	ENST00000556734.1	n.374+8446G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 250874 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000916

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461344 Hom.: 1 Cov.: 30 AF XY: 0.000287 AC XY: 209 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74460

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000172 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313G>A (p.E105K) alteration is located in exon 4 (coding exon 4) of the TOMM20L gene. This alteration results from a G to A substitution at nucleotide position 313, causing the glutamic acid (E) at amino acid position 105 to be replaced by a lysine (K). 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	0.090
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.034
Sift	Uncertain	0.011	D
Sift4G	Benign	0.37	T
Polyphen		0.012	B
Vest4		0.18
MVP		0.030
MPC		0.57
ClinPred		0.11	T
GERP RS		1.9
Varity_R		0.12
gMVP		0.18

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

Other links and lift over

dbSNP: rs141434824; hg19: chr14-58874094; COSMIC: COSV53621973; COSMIC: COSV53621973;