Genetic Variant NM_001096.3:c.2643-106T>C (chr17-41872288-A-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.2643-106T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,095,206 control chromosomes in the GnomAD database, including 314,702 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.76 ( 44035 hom., cov: 31)

Exomes 𝑓: 0.76 ( 270667 hom. )

Consequence

ACLY
NM_001096.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.714

Publications

11 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 (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001096.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACLY	NM_001096.3	MANE Select	c.2643-106T>C	intron	N/A	NP_001087.2
ACLY	NM_001303274.1		c.2805-106T>C	intron	N/A	NP_001290203.1	P53396
ACLY	NM_001303275.1		c.2775-106T>C	intron	N/A	NP_001290204.1	P53396

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACLY	ENST00000352035.7	TSL:1 MANE Select	c.2643-106T>C	intron	N/A	ENSP00000253792.2	P53396-1
ACLY	ENST00000590151.5	TSL:1	c.2643-106T>C	intron	N/A	ENSP00000466259.1	P53396-1
ACLY	ENST00000884509.1		c.2727-106T>C	intron	N/A	ENSP00000554568.1

Frequencies

GnomAD3 genomes

AF:

0.759

AC:

115308

AN:

151942

Hom.:

44003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.728

Gnomad AMI

AF:

0.826

Gnomad AMR

AF:

0.845

Gnomad ASJ

AF:

0.870

Gnomad EAS

AF:

0.823

Gnomad SAS

AF:

0.826

Gnomad FIN

AF:

0.628

Gnomad MID

AF:

0.804

Gnomad NFE

AF:

0.762

Gnomad OTH

AF:

0.783

GnomAD4 exome

AF:

0.755

AC:

712364

AN:

943146

Hom.:

270667

AF XY:

0.759

AC XY:

360807

AN XY:

475164

show subpopulations

African (AFR)

AF:

0.710

AC:

16310

AN:

22984

American (AMR)

AF:

0.876

AC:

28414

AN:

32450

Ashkenazi Jewish (ASJ)

AF:

0.867

AC:

16904

AN:

19486

East Asian (EAS)

AF:

0.839

AC:

28659

AN:

34174

South Asian (SAS)

AF:

0.826

AC:

52773

AN:

63890

European-Finnish (FIN)

AF:

0.659

AC:

22722

AN:

34466

Middle Eastern (MID)

AF:

0.822

AC:

3795

AN:

4618

European-Non Finnish (NFE)

AF:

0.741

AC:

509841

AN:

687970

Other (OTH)

AF:

0.764

AC:

32946

AN:

43108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

8218

16436

24653

32871

41089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10548

21096

31644

42192

52740

<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:

0.759

AC:

115387

AN:

152060

Hom.:

44035

Cov.:

AF XY:

0.757

AC XY:

56224

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.727

AC:

30151

AN:

41460

American (AMR)

AF:

0.846

AC:

12924

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.870

AC:

3018

AN:

3470

East Asian (EAS)

AF:

0.823

AC:

4258

AN:

5176

South Asian (SAS)

AF:

0.826

AC:

3987

AN:

4826

European-Finnish (FIN)

AF:

0.628

AC:

6627

AN:

10554

Middle Eastern (MID)

AF:

0.810

AC:

238

AN:

294

European-Non Finnish (NFE)

AF:

0.762

AC:

51780

AN:

67976

Other (OTH)

AF:

0.782

AC:

1651

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1442

2884

4327

5769

7211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.775

Hom.:

8703

Bravo

AF:

0.774

Asia WGS

AF:

0.818

AC:

2847

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.027

(source)

DANN

Benign

0.41

PhyloP100

-0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over