dbSNP rs2304497: ACLY:p.Glu175Asp (chr17-41909521-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001096.3(ACLY):c.525A>T(p.Glu175Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACLY
NM_001096.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

0 publications found

Variant links:

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]

ACLY links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020419836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACLY	NM_001096.3 link	c.525A>T	p.Glu175Asp	missense_variant	Exon 5 of 29	ENST00000352035.7	NP_001087.2	P53396-1A0A024R1T9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACLY	ENST00000352035.7 link	c.525A>T	p.Glu175Asp	missense_variant	Exon 5 of 29	1	NM_001096.3	ENSP00000253792.2		P53396-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.31

T;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.82

.;T;T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.34

N;N;N;N

PhyloP100

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.56

N;.;N;N

REVEL

Benign

0.069

Sift

Benign

0.79

T;.;T;T

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.067

MutPred

0.27

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.30

MPC

0.36

ClinPred

0.022

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.13

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over