rs1180614918

Variant names:

• chr11-86442917-T-A
• rs1180614918
• ENST00000393324.7:c.1557A>T

Variant summary

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

The ENST00000543262.6(ME3):​c.1557A>T​(p.Gln519His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,457,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q519K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ME3 ENST00000543262.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.443
• 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=0.13925382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME3	NM_001014811.2	c.1557A>T	p.Gln519His	missense_variant, splice_region_variant	Exon 13 of 14		NP_001014811.1
ME3	NM_001161586.3	c.1557A>T	p.Gln519His	missense_variant, splice_region_variant	Exon 14 of 15		NP_001155058.1
ME3	NM_001351934.2	c.1557A>T	p.Gln519His	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.1557A>T	p.Gln519His	missense_variant, splice_region_variant	Exon 13 of 14	1		ENSP00000376998.2
ME3	ENST00000543262.6	c.1557A>T	p.Gln519His	missense_variant, splice_region_variant	Exon 14 of 15	1		ENSP00000440246.1
ENSG00000254733	ENST00000524610.2	n.383+10275T>A		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1	n.423+10275T>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250640 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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1457622 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725348

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00000992 AC: 11 AN: 1108552

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1557A>T (p.Q519H) alteration is located in exon 14 (coding exon 13) of the ME3 gene. This alteration results from a A to T substitution at nucleotide position 1557, causing the glutamine (Q) at amino acid position 519 to be replaced by a histidine (H). 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.53	.;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		-0.44
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.96	N;N;N
REVEL	Benign	0.099
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.032	D;D;.
Polyphen		0.0	B;B;.
Vest4		0.11
MutPred		0.64		Loss of disorder (P = 0.2249);Loss of disorder (P = 0.2249);Loss of disorder (P = 0.2249);
MVP		0.58
MPC		0.47
ClinPred		0.49	T
GERP RS		1.9
Varity_R		0.13
gMVP		0.71
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1180614918; hg19: chr11-86153959;