14-58407343-A-G

Variant names:

• chr14-58407343-A-G
• rs2036075515
• NM_207377.3:c.280A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207377.3(TOMM20L):​c.280A>G​(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. I94F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOMM20L NM_207377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409
• 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]

ENSG00000258378 (HGNC:):

TIMM9 (HGNC:11819): (translocase of inner mitochondrial membrane 9) TIMM9 belongs to a family of evolutionarily conserved proteins that are organized in heterooligomeric complexes in the mitochondrial intermembrane space. These proteins mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040943474).

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.280A>G	p.Ile94Val	missense	Exon 4 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.280A>G	p.Ile94Val	missense	Exon 4 of 5	ENSP00000354204.2	Q6UXN7
	TOMM20L	ENST00000557754.1	TSL:1	n.198A>G		non_coding_transcript_exon	Exon 3 of 4	ENSP00000451683.1	G3V4A4
	ENSG00000258378	ENST00000556734.1	TSL:3	n.374+8413A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.6
DANN	Benign	0.42
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.2	N
PhyloP100		0.41
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.62		Gain of MoRF binding (P = 0.1003)
MVP		0.014
MPC		0.42
ClinPred		0.090	T
GERP RS		1.9
Varity_R		0.076
gMVP		0.071
Mutation Taster		=95/5	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: rs2036075515; hg19: chr14-58874061;