chr11-86450346-C-G

Variant names:

• chr11-86450346-C-G
• rs1042780
• NM_001161586.3:c.972G>C

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 24 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:58438):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006680.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME3	ENST00000543262.6	TSL:1 MANE Select	c.972G>C	p.Lys324Asn	missense	Exon 9 of 15	ENSP00000440246.1
	ME3	ENST00000393324.7	TSL:1	c.972G>C	p.Lys324Asn	missense	Exon 8 of 14	ENSP00000376998.2
	ME3	ENST00000875290.1		c.1131G>C	p.Lys377Asn	missense	Exon 10 of 16	ENSP00000545349.1

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

GnomAD2 exomes AF: 0.320 AC: 80155 AN: 250538 AF XY: 0.325

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 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

African (AFR) AF: 0.225 AC: 7516 AN: 33476

American (AMR) AF: 0.360 AC: 16099 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 9367 AN: 26128

East Asian (EAS) AF: 0.208 AC: 8262 AN: 39690

South Asian (SAS) AF: 0.381 AC: 32886 AN: 86210

European-Finnish (FIN) AF: 0.229 AC: 12222 AN: 53370

Middle Eastern (MID) AF: 0.376 AC: 2171 AN: 5768

European-Non Finnish (NFE) AF: 0.326 AC: 362958 AN: 1111732

Other (OTH) AF: 0.320 AC: 19316 AN: 60384

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

African (AFR) AF: 0.231 AC: 9605 AN: 41508

American (AMR) AF: 0.373 AC: 5709 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1240 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1378 AN: 5172

South Asian (SAS) AF: 0.370 AC: 1786 AN: 4822

European-Finnish (FIN) AF: 0.221 AC: 2340 AN: 10580

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22344 AN: 67974

Other (OTH) AF: 0.332 AC: 703 AN: 2116

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 v4.9

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
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.019
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.0080	B
Vest4		0.18
MutPred		0.18		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
Mutation Taster		=94/6	polymorphism (auto)

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

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