ENST00000393324.7:c.1742C>T

Variant names:

• chr11-86441352-G-A
• ENST00000393324.7:c.1742C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000393324.7(ME3):​c.1742C>T​(p.Thr581Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ME3 ENST00000393324.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 0 publications found

Genes affected

ME3 (HGNC:6985): (malic enzyme 3) Malic enzyme catalyzes the oxidative decarboxylation of malate to pyruvate using either NAD+ or NADP+ as a cofactor. Mammalian tissues contain 3 distinct isoforms of malic enzyme: a cytosolic NADP(+)-dependent isoform, a mitochondrial NADP(+)-dependent isoform, and a mitochondrial NAD(+)-dependent isoform. This gene encodes a mitochondrial NADP(+)-dependent isoform. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000254733 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30841416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME3	NM_001014811.2	c.1742C>T	p.Thr581Ile	missense_variant	Exon 14 of 14		NP_001014811.1
ME3	NM_001161586.3	c.1742C>T	p.Thr581Ile	missense_variant	Exon 15 of 15		NP_001155058.1
ME3	NM_001351934.2	c.1742C>T	p.Thr581Ile	missense_variant	Exon 15 of 15		NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME3	ENST00000393324.7	c.1742C>T	p.Thr581Ile	missense_variant	Exon 14 of 14	1		ENSP00000376998.2
ME3	ENST00000543262.6	c.1742C>T	p.Thr581Ile	missense_variant	Exon 15 of 15	1		ENSP00000440246.1
ENSG00000254733	ENST00000524610.2	n.383+8710G>A		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1	n.423+8710G>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1742C>T (p.T581I) alteration is located in exon 15 (coding exon 14) of the ME3 gene. This alteration results from a C to T substitution at nucleotide position 1742, causing the threonine (T) at amino acid position 581 to be replaced by an isoleucine (I). 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	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		4.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.061
Sift	Benign	0.056	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.27	B;B
Vest4		0.27
MutPred		0.32		Loss of phosphorylation at T581 (P = 0.0387);Loss of phosphorylation at T581 (P = 0.0387);
MVP		0.74
MPC		0.64
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.26
gMVP		0.58
Mutation Taster		=70/30	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

hg19: chr11-86152394;