ENST00000393324.7:c.1660G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000393324.7(ME3):c.1660G>A(p.Asp554Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 1,585,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

ME3
ENST00000393324.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07014504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ME3	NM_001014811.2 link	c.1660G>A	p.Asp554Asn	missense_variant	Exon 14 of 14	NP_001014811.1	Q16798-1Q6TCH8
ME3	NM_001161586.3 link	c.1660G>A	p.Asp554Asn	missense_variant	Exon 15 of 15	NP_001155058.1	Q16798-1B2R995
ME3	NM_001351934.2 link	c.1660G>A	p.Asp554Asn	missense_variant	Exon 15 of 15	NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ME3	ENST00000393324.7 link	c.1660G>A	p.Asp554Asn	missense_variant	Exon 14 of 14	1	ENSP00000376998.2	Q16798-1
ME3	ENST00000543262.6 link	c.1660G>A	p.Asp554Asn	missense_variant	Exon 15 of 15	1	ENSP00000440246.1	Q16798-1
ENSG00000254733	ENST00000524610.2 link	n.383+8792C>T		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1 link	n.423+8792C>T		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000120

AC:

AN:

225624

AF XY:

0.0000901

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000702

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000953

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000970

AC:

139

AN:

1433242

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

712574

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31962

American (AMR)

AF:

0.00

AC:

AN:

38184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24178

East Asian (EAS)

AF:

0.00107

AC:

AN:

39364

South Asian (SAS)

AF:

0.000247

AC:

AN:

80966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.0000663

AC:

AN:

1101396

Other (OTH)

AF:

0.0000508

AC:

AN:

59038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41510

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000821

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1660G>A (p.D554N) alteration is located in exon 15 (coding exon 14) of the ME3 gene. This alteration results from a G to A substitution at nucleotide position 1660, causing the aspartic acid (D) at amino acid position 554 to be replaced by an asparagine (N). 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

0.12

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.070

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;.

PhyloP100

1.5

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.024

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.19

T;T;.

Polyphen

0.024

B;B;.

Vest4

0.17

MutPred

0.50

Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);

MVP

0.47

MPC

0.49

ClinPred

0.018

GERP RS

2.5

Varity_R

0.081

gMVP

0.49

Mutation Taster

=97/3

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.

ENST00000393324.7:c.1660G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over