ENST00000393324.7:c.1555C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000393324.7(ME3):c.1555C>G(p.Gln519Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,457,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q519H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ME3
ENST00000393324.7 missense, splice_region

Scores

Splicing: ADA: 0.0009577

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.69

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12454057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ME3	NM_001014811.2 link	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 13 of 14	NP_001014811.1	Q16798-1Q6TCH8
ME3	NM_001161586.3 link	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 14 of 15	NP_001155058.1	Q16798-1B2R995
ME3	NM_001351934.2 link	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 14 of 15	NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ME3	ENST00000393324.7 link	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 13 of 14	1	ENSP00000376998.2	Q16798-1
ME3	ENST00000543262.6 link	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 14 of 15	1	ENSP00000440246.1	Q16798-1
ENSG00000254733	ENST00000524610.2 link	n.383+10277G>C		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1 link	n.423+10277G>C		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250576

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1457144

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725122

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33370

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108122

Other (OTH)

AF:

0.00

AC:

AN:

60206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.040428), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.053

T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.015

N;N;.

PhyloP100

1.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.15

N;N;N

REVEL

Benign

0.097

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.26

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.26

MutPred

0.55

Gain of disorder (P = 0.0881);Gain of disorder (P = 0.0881);Gain of disorder (P = 0.0881);

MVP

0.55

MPC

0.54

ClinPred

0.14

GERP RS

3.6

Varity_R

0.11

gMVP

0.81

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00096

dbscSNV1_RF

Benign

0.15

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

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ENST00000393324.7:c.1555C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over