Variant chr12-125107188-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000316519.11(AACS):c.835C>G(p.Leu279Val) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,614,154 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

AACS
ENST00000316519.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024573177).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AACS	NM_023928.5 linkuse as main transcript	c.835C>G	p.Leu279Val	missense_variant	8/18	ENST00000316519.11	NP_076417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AACS	ENST00000316519.11 linkuse as main transcript	c.835C>G	p.Leu279Val	missense_variant	8/18	1	NM_023928.5	ENSP00000324842	P1	Q86V21-1

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000843

AC:

212

AN:

251398

Hom.:

AF XY:

0.000942

AC XY:

128

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00118

AC:

1722

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

820

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00202

Gnomad4 NFE exome

AF:

0.00136

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152334

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000614

Hom.:

Bravo

AF:

0.000635

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000771

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

Feb 16, 2023

The c.835C>G (p.L279V) alteration is located in exon 8 (coding exon 8) of the AACS gene. This alteration results from a C to G substitution at nucleotide position 835, causing the leucine (L) at amino acid position 279 to be replaced by a valine (V). 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

0.14

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.030

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.65

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

REVEL

Benign

0.13

Sift

Benign

0.25

Sift4G

Benign

0.18

Polyphen

0.72

Vest4

0.60

MVP

0.23

MPC

0.33

ClinPred

0.073

GERP RS

5.5

Varity_R

0.37

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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