chr20-25021451-C-G

Position:

• chr20-25021451-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032501.4(ACSS1):​c.1046G>C​(p.Gly349Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACSS1 NM_032501.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSS1	NM_032501.4	c.1046G>C	p.Gly349Ala	missense_variant	6/14	ENST00000323482.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSS1	ENST00000323482.9	c.1046G>C	p.Gly349Ala	missense_variant	6/14	1	NM_032501.4	P1
ACSS1	ENST00000432802.6	c.1046G>C	p.Gly349Ala	missense_variant	6/12	2
ACSS1	ENST00000537502.5	c.683G>C	p.Gly228Ala	missense_variant	5/13	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Feb 01, 2023

The c.1046G>C (p.G349A) alteration is located in exon 6 (coding exon 6) of the ACSS1 gene. This alteration results from a G to C substitution at nucleotide position 1046, causing the glycine (G) at amino acid position 349 to be replaced by an alanine (A). 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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	2.0	.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	.;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.017	.;D;D
Sift4G	Uncertain	0.026	D;T;T
Polyphen		0.99	.;.;D
Vest4		0.95
MutPred		0.91		.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.65
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr20-25002087;