chr11-86441434-C-A

Variant names:

• chr11-86441434-C-A
• rs776037003
• ENST00000393324.7:c.1660G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000543262.6(ME3):​c.1660G>T​(p.Asp554Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. D554N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ME3 ENST00000543262.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4138432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME3	NM_001014811.2	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 14 of 14		NP_001014811.1
ME3	NM_001161586.3	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 15 of 15		NP_001155058.1
ME3	NM_001351934.2	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 15 of 15		NP_001338863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME3	ENST00000393324.7	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 14 of 14	1		ENSP00000376998.2
ME3	ENST00000543262.6	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 15 of 15	1		ENSP00000440246.1
ENSG00000254733	ENST00000524610.2	n.383+8792C>A		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1	n.423+8792C>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433240 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712572

⚠️ 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: 31962

American (AMR) AF: 0.00 AC: 0 AN: 38184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24178

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101396

Other (OTH) AF: 0.00 AC: 0 AN: 59038

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		0.92	P;P;.
Vest4		0.46
MutPred		0.57		Gain of MoRF binding (P = 0.0568);Gain of MoRF binding (P = 0.0568);Gain of MoRF binding (P = 0.0568);
MVP		0.61
MPC		0.97
ClinPred		0.96	D
GERP RS		2.5
Varity_R		0.76
gMVP		0.74
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs776037003; hg19: chr11-86152476;