11-86487422-G-C

Position:

• chr11-86487422-G-C

Variant summary

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

The NM_006680.3(ME3):​c.724C>G​(p.Leu242Val) variant causes a missense change involving the alteration of a non-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: 32)
• Consequence: ME3 NM_006680.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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]

ME3 (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/exons	MANE	Protein	UniProt
ME3	NM_001014811.2	c.724C>G	p.Leu242Val	missense_variant	6/14		NP_001014811.1
ME3	NM_001161586.3	c.724C>G	p.Leu242Val	missense_variant	7/15		NP_001155058.1
ME3	NM_001351934.2	c.724C>G	p.Leu242Val	missense_variant	7/15		NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME3	ENST00000543262.6	c.724C>G	p.Leu242Val	missense_variant	7/15	1		ENSP00000440246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 18, 2024

The c.724C>G (p.L242V) alteration is located in exon 7 (coding exon 6) of the ME3 gene. This alteration results from a C to G substitution at nucleotide position 724, causing the leucine (L) at amino acid position 242 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.2	M;M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.028	D;D;D;D
Sift4G	Uncertain	0.050	T;T;.;D
Polyphen		0.49	P;P;.;.
Vest4		0.78
MutPred		0.72		Gain of methylation at K247 (P = 0.1114);Gain of methylation at K247 (P = 0.1114);Gain of methylation at K247 (P = 0.1114);.;
MVP		0.73
MPC		0.75
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.30
gMVP		0.84

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: rs1951758814; hg19: chr11-86198464; COSMIC: COSV60164245;