9-37592474-A-G

Variant names:

• chr9-37592474-A-G
• NM_001001790.3:c.59T>C

Variant summary

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

The NM_001001790.3(TOMM5):​c.59T>C​(p.Met20Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TOMM5 NM_001001790.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

Genes affected

TOMM5 (HGNC:31369): (translocase of outer mitochondrial membrane 5) Predicted to be involved in protein targeting to mitochondrion. Located in mitochondrion. Part of mitochondrial outer membrane translocase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255872 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM5	NM_001001790.3	c.59T>C	p.Met20Thr	missense_variant	Exon 1 of 2	ENST00000321301.7	NP_001001790.1
TOMM5	NM_001134484.2	c.59T>C	p.Met20Thr	missense_variant	Exon 1 of 2		NP_001127956.1
TOMM5	NM_001134485.2	c.59T>C	p.Met20Thr	missense_variant	Exon 1 of 2		NP_001127957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM5	ENST00000321301.7	c.59T>C	p.Met20Thr	missense_variant	Exon 1 of 2	1	NM_001001790.3	ENSP00000313584.6
ENSG00000255872	ENST00000540557.1	n.*1136-3542T>C		intron_variant	Intron 11 of 11	5		ENSP00000457548.1
ENSG00000256966	ENST00000537239.2	n.-5T>C		upstream_gene_variant		5		ENSP00000457849.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59T>C (p.M20T) alteration is located in exon 1 (coding exon 1) of the TOMM5 gene. This alteration results from a T to C substitution at nucleotide position 59, causing the methionine (M) at amino acid position 20 to be replaced by a threonine (T). 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	0.94
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	.;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	-0.23	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.055	T;T;D;D
Sift4G	Uncertain	0.042	D;T;D;D
Polyphen		0.89	.;P;.;.
Vest4		0.85
MutPred		0.39		Loss of catalytic residue at M20 (P = 0.0015);Loss of catalytic residue at M20 (P = 0.0015);Loss of catalytic residue at M20 (P = 0.0015);Loss of catalytic residue at M20 (P = 0.0015);
MVP		0.53
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.85
gMVP		0.071

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: chr9-37592471;