chr20-25007850-T-C

Position:

• chr20-25007850-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032501.4(ACSS1):​c.1982A>G​(p.Asp661Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSS1 NM_032501.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

Genes affected

ACSS1 (HGNC:16091): (acyl-CoA synthetase short chain family member 1) This gene encodes a mitochondrial acetyl-CoA synthetase enzyme. A similar protein in mice plays an important role in the tricarboxylic acid cycle by catalyzing the conversion of acetate to acetyl CoA. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACSS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSS1	NM_032501.4	c.1982A>G	p.Asp661Gly	missense_variant	14/14	ENST00000323482.9	NP_115890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSS1	ENST00000323482.9	c.1982A>G	p.Asp661Gly	missense_variant	14/14	1	NM_032501.4	ENSP00000316924.4
ACSS1	ENST00000484396.1	n.3149A>G		non_coding_transcript_exon_variant	2/2	1
ACSS1	ENST00000537502.5	c.1619A>G	p.Asp540Gly	missense_variant	13/13	2		ENSP00000439304.2
ACSS1	ENST00000432802.6	c.1663-925A>G		intron_variant		2		ENSP00000388793.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.1982A>G (p.D661G) alteration is located in exon 14 (coding exon 14) of the ACSS1 gene. This alteration results from a A to G substitution at nucleotide position 1982, causing the aspartic acid (D) at amino acid position 661 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	4.6	.;H
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.8	.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.88
MutPred		0.62		.;Loss of solvent accessibility (P = 0.0477);
MVP		0.66
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-24988486;