17-41892284-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001096.3(ACLY):c.1765G>A(p.Ala589Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: ACLY NM_001096.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.83

Genes affected

ACLY (HGNC:115): (ATP citrate lyase) ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACLY
• BP4: Computational evidence support a benign effect (MetaRNN=0.16496202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACLY	NM_001096.3	c.1765G>A	p.Ala589Thr	missense_variant	16/29	ENST00000352035.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACLY	ENST00000352035.7	c.1765G>A	p.Ala589Thr	missense_variant	16/29	1	NM_001096.3	P3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Martin Pollak Laboratory, Beth Israel Deaconess Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.95
DEOGEN2	Uncertain	0.66	D;D;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.90	L;L;.;.;.
MutationTaster	Benign	0.83	D;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.59	N;.;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.023	D;.;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D
Polyphen		0.0050	B;B;.;.;.
Vest4		0.067
MutPred		0.68		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;.;.;
MVP		0.55
MPC		0.42
ClinPred		0.41	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.22
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs387907381; hg19: chr17-40048537;