ENST00000393324.7:c.1573T>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000393324.7(ME3):c.1573T>G(p.Ser525Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ME3
ENST00000393324.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.03

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2679656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ME3	NM_001014811.2 link	c.1573T>G	p.Ser525Ala	missense_variant	Exon 13 of 14	NP_001014811.1	Q16798-1Q6TCH8
ME3	NM_001161586.3 link	c.1573T>G	p.Ser525Ala	missense_variant	Exon 14 of 15	NP_001155058.1	Q16798-1B2R995
ME3	NM_001351934.2 link	c.1573T>G	p.Ser525Ala	missense_variant	Exon 14 of 15	NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ME3	ENST00000393324.7 link	c.1573T>G	p.Ser525Ala	missense_variant	Exon 13 of 14	1	ENSP00000376998.2	Q16798-1
ME3	ENST00000543262.6 link	c.1573T>G	p.Ser525Ala	missense_variant	Exon 14 of 15	1	ENSP00000440246.1	Q16798-1
ENSG00000254733	ENST00000524610.2 link	n.383+10259A>C		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1 link	n.423+10259A>C		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726602

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:

33450

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110894

Other (OTH)

AF:

0.00

AC:

AN:

60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1573T>G (p.S525A) alteration is located in exon 14 (coding exon 13) of the ME3 gene. This alteration results from a T to G substitution at nucleotide position 1573, causing the serine (S) at amino acid position 525 to be replaced by an alanine (A). 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

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

T;T;T

Eigen

Benign

0.048

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.86

.;D;D

M_CAP

Benign

0.0084

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;.

PhyloP100

5.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.054

T;T;.

Polyphen

0.0020

B;B;.

Vest4

0.28

MutPred

0.37

Loss of disorder (P = 0.0598);Loss of disorder (P = 0.0598);Loss of disorder (P = 0.0598);

MVP

0.65

MPC

0.43

ClinPred

0.87

GERP RS

5.6

Varity_R

0.37

gMVP

0.44

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over