11-86441434-C-T

Position:

chr11-86441434-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006680.3(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. 14/21 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
NM_006680.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

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:

ME3 (HGNC:):

ME3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
ME3	NM_001014811.2 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	14/14	NP_001014811.1	Q16798-1Q6TCH8
ME3	NM_001161586.3 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	15/15	NP_001155058.1	Q16798-1B2R995
ME3	NM_001351934.2 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	15/15	NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
ME3	ENST00000393324.7 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	14/14	1	ENSP00000376998.2	Q16798-1
ME3	ENST00000524826.8 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	15/15	1		Q16798-1E9PMB9
ME3	ENST00000543262.6 linkuse as main transcript	c.1660G>A	p.Asp554Asn	missense_variant	15/15	1	ENSP00000440246.1	Q16798-1
ENSG00000254733	ENST00000524610.1 linkuse as main transcript	n.268+8792C>T		intron_variant		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

GnomAD3 exomes

AF:

0.000120

AC:

AN:

225624

Hom.:

AF XY:

0.0000901

AC XY:

AN XY:

122110

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 SAS exome

AF:

0.000157

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

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00107

Gnomad4 SAS exome

AF:

0.000247

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000663

Gnomad4 OTH exome

AF:

0.0000508

GnomAD4 genome

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

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

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;.

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over