6-83211959-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002395.6(ME1):c.1684G>A(p.Glu562Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ME1 NM_002395.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

ME1 (HGNC:6983): (malic enzyme 1) This gene encodes a cytosolic, NADP-dependent enzyme that generates NADPH for fatty acid biosynthesis. The activity of this enzyme, the reversible oxidative decarboxylation of malate, links the glycolytic and citric acid cycles. The regulation of expression for this gene is complex. Increased expression can result from elevated levels of thyroid hormones or by higher proportions of carbohydrates in the diet. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.12482092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ME1	NM_002395.6	c.1684G>A	p.Glu562Lys	missense_variant	14/14	ENST00000369705.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ME1	ENST00000369705.4	c.1684G>A	p.Glu562Lys	missense_variant	14/14	1	NM_002395.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454924 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723750

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.1684G>A (p.E562K) alteration is located in exon 14 (coding exon 14) of the ME1 gene. This alteration results from a G to A substitution at nucleotide position 1684, causing the glutamic acid (E) at amino acid position 562 to be replaced by a lysine (K). 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	0.099
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.016
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.011	B
Vest4		0.19
MutPred		0.40		Gain of methylation at E562 (P = 0.0019);
MVP		0.47
MPC		0.043
ClinPred		0.18	T
GERP RS		3.0
Varity_R		0.082
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-83921678;