chr12-125107258-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000316519.11(AACS):​c.905A>T​(p.His302Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AACS
ENST00000316519.11 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.49
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]

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ACMG classification

Classification made for transcript

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, 0.916

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AACSNM_023928.5 linkuse as main transcriptc.905A>T p.His302Leu missense_variant 8/18 ENST00000316519.11 NP_076417.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AACSENST00000316519.11 linkuse as main transcriptc.905A>T p.His302Leu missense_variant 8/181 NM_023928.5 ENSP00000324842 P1Q86V21-1
AACSENST00000316543.14 linkuse as main transcriptn.782A>T non_coding_transcript_exon_variant 2/112
AACSENST00000441247.6 linkuse as main transcriptn.2120A>T non_coding_transcript_exon_variant 3/75
AACSENST00000537564.5 linkuse as main transcriptn.563A>T non_coding_transcript_exon_variant 4/44

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461424
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727026
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 submitterclinical testingAmbry GeneticsApr 07, 2022The c.905A>T (p.H302L) alteration is located in exon 8 (coding exon 8) of the AACS gene. This alteration results from a A to T substitution at nucleotide position 905, causing the histidine (H) at amino acid position 302 to be replaced by a leucine (L). 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
0.84
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.48
T
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Benign
-0.29
T
MutationAssessor
Pathogenic
4.2
H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-9.8
D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.98
MutPred
0.69
Loss of catalytic residue at H302 (P = 0.0166);
MVP
0.54
MPC
0.62
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.96
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: chr12-125591804; API