chr11-86442919-G-C

Variant names:

• chr11-86442919-G-C
• rs771830027
• ENST00000393324.7:c.1555C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000543262.6(ME3):​c.1555C>G​(p.Gln519Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,457,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q519H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ME3 ENST00000543262.6 missense, splice_region
• Scores: Splicing: ADA: 0.0009577
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

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]

ENSG00000254733 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12454057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME3	NM_001014811.2	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 13 of 14		NP_001014811.1
ME3	NM_001161586.3	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 14 of 15		NP_001155058.1
ME3	NM_001351934.2	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 14 of 15		NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME3	ENST00000393324.7	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 13 of 14	1		ENSP00000376998.2
ME3	ENST00000543262.6	c.1555C>G	p.Gln519Glu	missense_variant, splice_region_variant	Exon 14 of 15	1		ENSP00000440246.1
ENSG00000254733	ENST00000524610.2	n.383+10277G>C		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1	n.423+10277G>C		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250576 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1457144 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725122

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108122

Other (OTH) AF: 0.00 AC: 0 AN: 60206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.040428), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.053	T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.015	N;N;.
PhyloP100		1.7
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.26	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.26
MutPred		0.55		Gain of disorder (P = 0.0881);Gain of disorder (P = 0.0881);Gain of disorder (P = 0.0881);
MVP		0.55
MPC		0.54
ClinPred		0.14	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.81
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00096
dbscSNV1_RF	Benign	0.15
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

Other links and lift over

dbSNP: rs771830027; hg19: chr11-86153961;