Variant 11-86448176-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000393324.7(ME3):c.1211G>T(p.Arg404Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ME3
ENST00000393324.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.04

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ME3	NM_001161586.3 linkuse as main transcript	c.1211G>T	p.Arg404Met	missense_variant	11/15	ENST00000543262.6
ME3	NR_172888.1 linkuse as main transcript	n.1518G>T		non_coding_transcript_exon_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ME3	ENST00000543262.6 linkuse as main transcript	c.1211G>T	p.Arg404Met	missense_variant	11/15	1	NM_001161586.3	P1	Q16798-1
ME3	ENST00000393324.7 linkuse as main transcript	c.1211G>T	p.Arg404Met	missense_variant	10/14	1		P1	Q16798-1
	ENST00000524610.1 linkuse as main transcript	n.268+15534C>A		intron_variant, non_coding_transcript_variant		3
ME3	ENST00000530520.5 linkuse as main transcript	n.1232G>T		non_coding_transcript_exon_variant	10/11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135878

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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 20, 2023

The c.1211G>T (p.R404M) alteration is located in exon 11 (coding exon 10) of the ME3 gene. This alteration results from a G to T substitution at nucleotide position 1211, causing the arginine (R) at amino acid position 404 to be replaced by a methionine (M). 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

0.23

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

Cadd

Uncertain

Dann

Benign

0.96

DEOGEN2

Benign

0.27

T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

0.75

D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0050

D;D;.

Polyphen

0.85

P;P;.

Vest4

0.49

MutPred

0.47

Gain of methylation at K407 (P = 0.0498);Gain of methylation at K407 (P = 0.0498);Gain of methylation at K407 (P = 0.0498);

MVP

0.82

MPC

1.3

ClinPred

0.96

GERP RS

3.8

Varity_R

0.50

gMVP

0.63

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