14-58407351-C-A

Variant names:

• chr14-58407351-C-A
• NM_207377.3:c.288C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_207377.3(TOMM20L):​c.288C>A​(p.His96Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOMM20L NM_207377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.231

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM20L	NM_207377.3	c.288C>A	p.His96Gln	missense_variant	Exon 4 of 5	ENST00000360945.7	NP_997260.1
TOMM20L	XM_011536742.4	c.312C>A	p.His104Gln	missense_variant	Exon 4 of 5		XP_011535044.1
TOMM20L	XM_011536743.3	c.312C>A	p.His104Gln	missense_variant	Exon 4 of 5		XP_011535045.1
TOMM20L	XM_011536744.4	c.162C>A	p.His54Gln	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.288C>A	p.His96Gln	missense_variant	Exon 4 of 5	1	NM_207377.3	ENSP00000354204.2
TOMM20L	ENST00000557754.1	n.206C>A		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000451683.1
ENSG00000258378	ENST00000556734.1	n.374+8421C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.288C>A (p.H96Q) alteration is located in exon 4 (coding exon 4) of the TOMM20L gene. This alteration results from a C to A substitution at nucleotide position 288, causing the histidine (H) at amino acid position 96 to be replaced by a glutamine (Q). 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	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.0065
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.79		Loss of catalytic residue at I94 (P = 0.1224);
MVP		0.28
MPC		1.4
ClinPred		1.0	D
GERP RS		1.3
Varity_R		0.96
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-58874069;