9-37592502-G-T

Position:

• chr9-37592502-G-T

Variant summary

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

The NM_001001790.3(TOMM5):​c.31C>A​(p.Leu11Met) 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. 12/19 in silico tools predict a benign outcome for this variant. 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: 0.693

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]

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=0.15202552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMM5	NM_001001790.3	c.31C>A	p.Leu11Met	missense_variant	1/2	ENST00000321301.7	NP_001001790.1
TOMM5	NM_001134484.2	c.31C>A	p.Leu11Met	missense_variant	1/2		NP_001127956.1
TOMM5	NM_001134485.2	c.31C>A	p.Leu11Met	missense_variant	1/2		NP_001127957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM5	ENST00000321301.7	c.31C>A	p.Leu11Met	missense_variant	1/2	1	NM_001001790.3	ENSP00000313584	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.31C>A (p.L11M) alteration is located in exon 1 (coding exon 1) of the TOMM5 gene. This alteration results from a C to A substitution at nucleotide position 31, causing the leucine (L) at amino acid position 11 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	.;T;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.81	N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0030	.;B;.;.
Vest4		0.20
MutPred		0.18		Loss of methylation at K10 (P = 0.0359);Loss of methylation at K10 (P = 0.0359);Loss of methylation at K10 (P = 0.0359);Loss of methylation at K10 (P = 0.0359);
MVP		0.17
MPC		1.7
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.0082

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: rs1823123885; hg19: chr9-37592499;