Genetic Variant ACLY:p.Glu175Asp (chr17-41909521-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001096.3(ACLY):c.525A>C(p.Glu175Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,936 control chromosomes in the GnomAD database, including 11,379 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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: 𝑓 0.11 ( 949 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10430 hom. )

Consequence

ACLY
NM_001096.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

50 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011338592).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16097

AN:

152092

Hom.:

937

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0589

Gnomad ASJ

AF:

0.0389

Gnomad EAS

AF:

0.0632

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.0914

GnomAD2 exomes

AF:

0.102

AC:

25610

AN:

251330

AF XY:

0.103

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.0422

Gnomad ASJ exome

AF:

0.0398

Gnomad EAS exome

AF:

0.0610

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.0917

GnomAD4 exome

AF:

0.116

AC:

169775

AN:

1461726

Hom.:

10430

Cov.:

AF XY:

0.115

AC XY:

83766

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.101

AC:

3393

AN:

33470

American (AMR)

AF:

0.0444

AC:

1985

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

1101

AN:

26132

East Asian (EAS)

AF:

0.0596

AC:

2364

AN:

39696

South Asian (SAS)

AF:

0.104

AC:

8943

AN:

86252

European-Finnish (FIN)

AF:

0.173

AC:

9267

AN:

53420

Middle Eastern (MID)

AF:

0.0439

AC:

253

AN:

5766

European-Non Finnish (NFE)

AF:

0.122

AC:

135979

AN:

1111880

Other (OTH)

AF:

0.107

AC:

6490

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

7781

15561

23342

31122

38903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4928

9856

14784

19712

24640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.106

AC:

16144

AN:

152210

Hom.:

949

Cov.:

AF XY:

0.107

AC XY:

7959

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.102

AC:

4219

AN:

41534

American (AMR)

AF:

0.0587

AC:

898

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

135

AN:

3468

East Asian (EAS)

AF:

0.0630

AC:

326

AN:

5176

South Asian (SAS)

AF:

0.107

AC:

515

AN:

4826

European-Finnish (FIN)

AF:

0.180

AC:

1906

AN:

10588

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7871

AN:

68000

Other (OTH)

AF:

0.0923

AC:

195

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

737

1475

2212

2950

3687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.107

Hom.:

3971

Bravo

AF:

0.0959

TwinsUK

AF:

0.127

AC:

471

ALSPAC

AF:

0.125

AC:

483

ESP6500AA

AF:

0.0960

AC:

423

ESP6500EA

AF:

0.110

AC:

949

ExAC

AF:

0.104

AC:

12585

Asia WGS

AF:

0.0890

AC:

312

AN:

3478

EpiCase

AF:

0.104

EpiControl

AF:

0.100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.6

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.31

T;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.82

.;T;T;.

MetaRNN

Benign

0.0011

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N;N;N

PhyloP100

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.56

N;.;N;N

REVEL

Benign

0.070

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);

MPC

0.36

ClinPred

0.00087

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.13

gMVP

0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over