Variant 12-125114516-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_023928.5(AACS):c.955G>A(p.Gly319Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,613,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

AACS
NM_023928.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.38

Variant links:

Genes affected

AACS (HGNC:21298): (acetoacetyl-CoA synthetase) Predicted to enable acetoacetate-CoA ligase activity. Predicted to be involved in positive regulation of insulin secretion. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

AACS links:

AACS (HGNC:):

AACS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13648838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AACS	NM_023928.5 linkuse as main transcript	c.955G>A	p.Gly319Ser	missense_variant	9/18	ENST00000316519.11	NP_076417.2	Q86V21-1A0A024RBV2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AACS	ENST00000316519.11 linkuse as main transcript	c.955G>A	p.Gly319Ser	missense_variant	9/18	1	NM_023928.5	ENSP00000324842.6	Q86V21-1
AACS	ENST00000316543.14 linkuse as main transcript	n.832G>A		non_coding_transcript_exon_variant	3/11	2
AACS	ENST00000441247.6 linkuse as main transcript	n.2170G>A		non_coding_transcript_exon_variant	4/7	5
AACS	ENST00000539251.5 linkuse as main transcript	n.96G>A		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000156

AC:

AN:

250546

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135476

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461106

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000217

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000797

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000770

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.955G>A (p.G319S) alteration is located in exon 9 (coding exon 9) of the AACS gene. This alteration results from a G to A substitution at nucleotide position 955, causing the glycine (G) at amino acid position 319 to be replaced by a serine (S). 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

Benign

0.16

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.15

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.043

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

M_CAP

Benign

0.020

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.8

REVEL

Benign

0.19

Sift

Benign

0.71

Sift4G

Benign

0.85

Polyphen

0.89

Vest4

0.48

MVP

0.26

MPC

0.33

ClinPred

0.083

GERP RS

3.8

Varity_R

0.17

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over