17-41909521-T-G

Position:

• chr17-41909521-T-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ACLY	NM_001096.3	c.525A>C	p.Glu175Asp	missense_variant	5/29	ENST00000352035.7	NP_001087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACLY	ENST00000352035.7	c.525A>C	p.Glu175Asp	missense_variant	5/29	1	NM_001096.3	ENSP00000253792.2

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

GnomAD3 exomes AF: 0.102 AC: 25610 AN: 251330 Hom.: 1600 AF XY: 0.103 AC XY: 13988 AN XY: 135830

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 SAS exome AF: 0.106

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

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0444

Gnomad4 ASJ exome AF: 0.0421

Gnomad4 EAS exome AF: 0.0596

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.107

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

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0587

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.0630

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0923

Alfa AF: 0.105 Hom.: 1950

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	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.6
DANN	Benign	0.67
DEOGEN2	Benign	0.31	T;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.82	.;T;T;.
MetaRNN	Benign	0.0011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;N;N
PrimateAI	Benign	0.22	T
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	T
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)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2304497; hg19: chr17-40065774; COSMIC: COSV61250479; COSMIC: COSV61250479;