Genetic Variant ENST00000393324.7:c.972G>C (chr11-86450346-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000393324.7(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
ENST00000393324.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Variant links:

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 links:

ENSG00000254733 (HGNC:):

ENSG00000254733 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
ME3	NM_001014811.2 link	c.972G>C	p.Lys324Asn	missense_variant	Exon 8 of 14	NP_001014811.1	Q16798-1Q6TCH8
ME3	NM_001161586.3 link	c.972G>C	p.Lys324Asn	missense_variant	Exon 9 of 15	NP_001155058.1	Q16798-1B2R995
ME3	NM_001351934.2 link	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 link	c.972G>C	p.Lys324Asn	missense_variant	Exon 9 of 15	1		ENSP00000440246.1		Q16798-1

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45639

AN:

152016

Hom.:

7125

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.325

AC XY:

236148

AN XY:

727042

show subpopulations

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.:

AF XY:

0.298

AC XY:

22163

AN XY:

74368

show subpopulations

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

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

LIST_S2

Uncertain

0.92

.;D;D

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Uncertain

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over