14-58396057-C-T

Variant names:

• chr14-58396057-C-T
• rs762141525
• NM_207377.3:c.100C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_207377.3(TOMM20L):​c.100C>T​(p.Arg34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000793 in 1,261,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R34G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TOMM20L NM_207377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 0 publications found

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-DT (HGNC:55443): (TOMM20L divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207377.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM20L	NM_207377.3	MANE Select	c.100C>T	p.Arg34Cys	missense	Exon 1 of 5	NP_997260.1	Q6UXN7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM20L	ENST00000360945.7	TSL:1 MANE Select	c.100C>T	p.Arg34Cys	missense	Exon 1 of 5	ENSP00000354204.2	Q6UXN7
	TOMM20L	ENST00000557754.1	TSL:1	n.100C>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000451683.1	G3V4A4
	TOMM20L-DT	ENST00000556390.2	TSL:3	n.-231G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.93e-7 AC: 1 AN: 1261560 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 620894

African (AFR) AF: 0.00 AC: 0 AN: 25658

American (AMR) AF: 0.00 AC: 0 AN: 22896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19586

East Asian (EAS) AF: 0.00 AC: 0 AN: 30066

South Asian (SAS) AF: 0.00 AC: 0 AN: 51714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4862

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1011392

Other (OTH) AF: 0.0000200 AC: 1 AN: 50114

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.14
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.68		Loss of solvent accessibility (P = 0.0079)
MVP		0.43
MPC		1.7
ClinPred		1.0	D
GERP RS		2.7
PromoterAI		-0.037	Neutral
Varity_R		0.66
gMVP		0.31
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762141525; hg19: chr14-58862775;