20-34882934-G-A

Variant names:

• chr20-34882934-G-A
• rs57226725
• NM_018677.4:c.319G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018677.4(ACSS2):​c.319G>A​(p.Val107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V107L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACSS2 NM_018677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779
• Publications: 0 publications found

Genes affected

ACSS2 (HGNC:15814): (acyl-CoA synthetase short chain family member 2) This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP. Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23717216).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018677.4. 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
	ACSS2	NM_018677.4	MANE Select	c.319G>A	p.Val107Ile	missense	Exon 2 of 18	NP_061147.1	Q9NR19-1
	ACSS2	NM_001076552.3		c.319G>A	p.Val107Ile	missense	Exon 2 of 19	NP_001070020.2	Q9NR19-2
	ACSS2	NM_001242393.2		c.34G>A	p.Val12Ile	missense	Exon 2 of 18	NP_001229322.1	Q4G0E8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSS2	ENST00000360596.7	TSL:1 MANE Select	c.319G>A	p.Val107Ile	missense	Exon 2 of 18	ENSP00000353804.2	Q9NR19-1
	ACSS2	ENST00000484354.1	TSL:5	c.295G>A	p.Val99Ile	missense	Exon 2 of 3	ENSP00000419167.1	C9JXD9
	ACSS2	ENST00000871370.1		c.319G>A	p.Val107Ile	missense	Exon 2 of 20	ENSP00000541429.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459478 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725838

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111328

Other (OTH) AF: 0.00 AC: 0 AN: 60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.082
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.45	N
PhyloP100		0.78
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.12
Sift	Benign	0.053	T
Sift4G	Uncertain	0.055	T
Polyphen		0.0030	B
Vest4		0.098
MutPred		0.63		Loss of helix (P = 0.2271)
MVP		0.49
MPC		0.16
ClinPred		0.69	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.053
gMVP		0.25
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs57226725; hg19: chr20-33470737;