rs1042780

Variant names:

• chr11-86450346-C-G
• rs1042780
• ENST00000393324.7:c.972G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006680.3(ME3):​c.972G>C​(p.Lys324Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,613,612 control chromosomes in the GnomAD database, including 84,221 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (7129 hom., cov: 33)
  • Exomes 𝑓: 0.32 (77092 hom.)
• Consequence: ME3 NM_006680.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023363233).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME3	NM_001014811.2	c.972G>C	p.Lys324Asn	missense_variant	Exon 8 of 14		NP_001014811.1
ME3	NM_001161586.3	c.972G>C	p.Lys324Asn	missense_variant	Exon 9 of 15		NP_001155058.1
ME3	NM_001351934.2	c.972G>C	p.Lys324Asn	missense_variant	Exon 9 of 15		NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME3	ENST00000543262.6	c.972G>C	p.Lys324Asn	missense_variant	Exon 9 of 15	1		ENSP00000440246.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45639 AN: 152016 Hom.: 7125 Cov.: 33

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.320 AC: 80155 AN: 250538 Hom.: 13148 AF XY: 0.325 AC XY: 44089 AN XY: 135452

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.355

Gnomad EAS exome AF: 0.267

Gnomad SAS exome AF: 0.379

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.322 AC: 470797 AN: 1461476 Hom.: 77092 Cov.: 37 AF XY: 0.325 AC XY: 236148 AN XY: 727042

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.300 AC: 45663 AN: 152136 Hom.: 7129 Cov.: 33 AF XY: 0.298 AC XY: 22163 AN XY: 74368

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.370

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.332

Alfa AF: 0.325 Hom.: 6363

Bravo AF: 0.305

TwinsUK AF: 0.318 AC: 1179

ALSPAC AF: 0.344 AC: 1326

ESP6500AA AF: 0.234 AC: 1029

ESP6500EA AF: 0.336 AC: 2887

ExAC AF: 0.314 AC: 38118

Asia WGS AF: 0.298 AC: 1041 AN: 3478

EpiCase AF: 0.340

EpiControl AF: 0.351

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;D;D
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.18	T;T;.
Polyphen		0.0080	B;B;.
Vest4		0.18
MutPred		0.18		Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);
MPC		0.60
ClinPred		0.012	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.76

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: rs1042780; hg19: chr11-86161388; COSMIC: COSV62770737;