14-58396023-C-A

Variant names:

• chr14-58396023-C-A
• rs752436646
• NM_207377.3:c.66C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207377.3(TOMM20L):​c.66C>A​(p.Phe22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,301,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TOMM20L NM_207377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11052871).

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.66C>A	p.Phe22Leu	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.66C>A	p.Phe22Leu	missense	Exon 1 of 5	ENSP00000354204.2	Q6UXN7
	TOMM20L	ENST00000557754.1	TSL:1	n.66C>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000451683.1	G3V4A4
	TOMM20L-DT	ENST00000556390.2	TSL:3	n.-197G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 161380 AF XY: 0.0000108

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1301258 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644340

African (AFR) AF: 0.00 AC: 0 AN: 26664

American (AMR) AF: 0.00 AC: 0 AN: 27614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21284

East Asian (EAS) AF: 0.00 AC: 0 AN: 30522

South Asian (SAS) AF: 0.0000326 AC: 2 AN: 61296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5052

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1029996

Other (OTH) AF: 0.00 AC: 0 AN: 51880

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000173 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.22
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.058
Sift	Benign	0.14	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.31
MutPred		0.59		Loss of sheet (P = 0.0817)
MVP		0.030
MPC		0.59
ClinPred		0.24	T
GERP RS		0.84
PromoterAI		-0.12	Neutral
Varity_R		0.30
gMVP		0.17
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs752436646; hg19: chr14-58862741;