11-86487400-T-G

Position:

• chr11-86487400-T-G

Variant summary

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

The NM_006680.3(ME3):​c.746A>C​(p.Gln249Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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: 6.8e-7 (0 hom.)
• Consequence: ME3 NM_006680.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 (HGNC:):

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=0.1636506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ME3	NM_001014811.2	c.746A>C	p.Gln249Pro	missense_variant	6/14		NP_001014811.1
ME3	NM_001161586.3	c.746A>C	p.Gln249Pro	missense_variant	7/15		NP_001155058.1
ME3	NM_001351934.2	c.746A>C	p.Gln249Pro	missense_variant	7/15		NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME3	ENST00000543262.6	c.746A>C	p.Gln249Pro	missense_variant	7/15	1		ENSP00000440246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 8.99e-7

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

Dec 11, 2023

The c.746A>C (p.Q249P) alteration is located in exon 7 (coding exon 6) of the ME3 gene. This alteration results from a A to C substitution at nucleotide position 746, causing the glutamine (Q) at amino acid position 249 to be replaced by a proline (P). 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	0.074
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;N;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.23	T;T;.;T
Polyphen		0.0	B;B;.;.
Vest4		0.33
MutPred		0.64		Gain of catalytic residue at Q249 (P = 0.0984);Gain of catalytic residue at Q249 (P = 0.0984);Gain of catalytic residue at Q249 (P = 0.0984);.;
MVP		0.30
MPC		0.61
ClinPred		0.17	T
GERP RS		-3.0
Varity_R		0.24
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-86198442;