chr14-58407343-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207377.3(TOMM20L):​c.280A>T​(p.Ile94Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,444 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TOMM20L NM_207377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.409

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21304366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM20L	NM_207377.3	c.280A>T	p.Ile94Phe	missense_variant	Exon 4 of 5	ENST00000360945.7	NP_997260.1
TOMM20L	XM_011536742.4	c.304A>T	p.Ile102Phe	missense_variant	Exon 4 of 5		XP_011535044.1
TOMM20L	XM_011536743.3	c.304A>T	p.Ile102Phe	missense_variant	Exon 4 of 5		XP_011535045.1
TOMM20L	XM_011536744.4	c.154A>T	p.Ile52Phe	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.280A>T	p.Ile94Phe	missense_variant	Exon 4 of 5	1	NM_207377.3	ENSP00000354204.2
TOMM20L	ENST00000557754.1	n.198A>T		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000451683.1
ENSG00000258378	ENST00000556734.1	n.374+8413A>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456444 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724532

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280A>T (p.I94F) alteration is located in exon 4 (coding exon 4) of the TOMM20L gene. This alteration results from a A to T substitution at nucleotide position 280, causing the isoleucine (I) at amino acid position 94 to be replaced by a phenylalanine (F). 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.62
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.068
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.73		Loss of MoRF binding (P = 0.1259);
MVP		0.014
MPC		0.79
ClinPred		0.068	T
GERP RS		1.9
Varity_R		0.21
gMVP		0.44

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: rs2036075515; hg19: chr14-58874061;