chr11-86441434-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000543262.6(ME3):​c.1660G>A​(p.Asp554Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 1,585,444 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: ME3 ENST00000543262.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07014504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME3	NM_001014811.2	c.1660G>A	p.Asp554Asn	missense_variant	Exon 14 of 14		NP_001014811.1
ME3	NM_001161586.3	c.1660G>A	p.Asp554Asn	missense_variant	Exon 15 of 15		NP_001155058.1
ME3	NM_001351934.2	c.1660G>A	p.Asp554Asn	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>A	p.Asp554Asn	missense_variant	Exon 14 of 14	1		ENSP00000376998.2
ME3	ENST00000543262.6	c.1660G>A	p.Asp554Asn	missense_variant	Exon 15 of 15	1		ENSP00000440246.1
ENSG00000254733	ENST00000524610.2	n.383+8792C>T		intron_variant	Intron 2 of 2	3
ENSG00000254733	ENST00000758792.1	n.423+8792C>T		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 27 AN: 225624 AF XY: 0.0000901

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000702

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000970 AC: 139 AN: 1433242 Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 78 AN XY: 712574

African (AFR) AF: 0.0000313 AC: 1 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: 0.00107 AC: 42 AN: 39364

South Asian (SAS) AF: 0.000247 AC: 20 AN: 80966

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: 0.0000663 AC: 73 AN: 1101396

Other (OTH) AF: 0.0000508 AC: 3 AN: 59038

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74424

African (AFR) AF: 0.0000482 AC: 2 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000821 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1660G>A (p.D554N) alteration is located in exon 15 (coding exon 14) of the ME3 gene. This alteration results from a G to A substitution at nucleotide position 1660, causing the aspartic acid (D) at amino acid position 554 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.
PhyloP100		1.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.024
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.19	T;T;.
Polyphen		0.024	B;B;.
Vest4		0.17
MutPred		0.50		Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);
MVP		0.47
MPC		0.49
ClinPred		0.018	T
GERP RS		2.5
Varity_R		0.081
gMVP		0.49
Mutation Taster		=97/3	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: rs776037003; hg19: chr11-86152476; COSMIC: COSV107450407; COSMIC: COSV107450407;