11-86671833-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000393324.7(ME3):c.112C>T(p.Pro38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,770 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ME3 ENST00000393324.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.91

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033061117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ME3	NM_001161586.3	c.112C>T	p.Pro38Ser	missense_variant	2/15	ENST00000543262.6
ME3	NR_172888.1	n.419C>T		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ME3	ENST00000543262.6	c.112C>T	p.Pro38Ser	missense_variant	2/15	1	NM_001161586.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441770 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717182

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 16, 2023

The c.112C>T (p.P38S) alteration is located in exon 2 (coding exon 1) of the ME3 gene. This alteration results from a C to T substitution at nucleotide position 112, causing the proline (P) at amino acid position 38 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.065
Dann	Benign	0.93
DEOGEN2	Benign	0.045	T;T;T;.;T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.036	N
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.033	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.86	N;N;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;.;.;.;.;T
Polyphen		0.0	B;B;.;.;.;.;.
Vest4		0.030
MutPred		0.26		Gain of glycosylation at P38 (P = 0.0266);Gain of glycosylation at P38 (P = 0.0266);Gain of glycosylation at P38 (P = 0.0266);Gain of glycosylation at P38 (P = 0.0266);Gain of glycosylation at P38 (P = 0.0266);Gain of glycosylation at P38 (P = 0.0266);Gain of glycosylation at P38 (P = 0.0266);
MVP		0.14
MPC		0.50
ClinPred		0.088	T
GERP RS		-10
Varity_R		0.021
gMVP		0.17

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: chr11-86382875;