17-41909521-T-G

Variant names:

• chr17-41909521-T-G
• rs2304497
• NM_001096.3:c.525A>C
• ACLY p.Glu175Asp

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 51 publications found

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

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACLY	NM_001096.3	MANE Select	c.525A>C	p.Glu175Asp	missense	Exon 5 of 29	NP_001087.2
	ACLY	NM_001303274.1		c.687A>C	p.Glu229Asp	missense	Exon 5 of 29	NP_001290203.1	P53396
	ACLY	NM_001303275.1		c.687A>C	p.Glu229Asp	missense	Exon 5 of 28	NP_001290204.1	P53396

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACLY	ENST00000352035.7	TSL:1 MANE Select	c.525A>C	p.Glu175Asp	missense	Exon 5 of 29	ENSP00000253792.2	P53396-1
	ACLY	ENST00000590151.5	TSL:1	c.525A>C	p.Glu175Asp	missense	Exon 5 of 29	ENSP00000466259.1	P53396-1
	ACLY	ENST00000884509.1		c.609A>C	p.Glu203Asp	missense	Exon 6 of 30	ENSP00000554568.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16097 AN: 152092 Hom.: 937 Cov.: 32

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

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.: 32 AF XY: 0.115 AC XY: 83766 AN XY: 727174

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

GnomAD4 genome AF: 0.106 AC: 16144 AN: 152210 Hom.: 949 Cov.: 32 AF XY: 0.107 AC XY: 7959 AN XY: 74408

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: 9 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7871 AN: 68000

Other (OTH) AF: 0.0923 AC: 195 AN: 2112

Alfa AF: 0.107 Hom.: 3971

Bravo AF: 0.0959

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.6
DANN	Benign	0.67
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.070
Sift	Benign	0.79	T
Sift4G	Benign	0.63	T
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)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2304497;

hg19: chr17-40065774;

COSMIC: COSV61250479;

COSMIC: COSV61250479;