6-159778677-G-T

Variant names:

Variant summary

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

The NM_005891.3(ACAT2):c.1042G>T(p.Ala348Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

ACAT2
NM_005891.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

ACAT2 (HGNC:94): (acetyl-CoA acetyltransferase 2) The product of this gene is an enzyme involved in lipid metabolism, and it encodes cytosolic acetoacetyl-CoA thiolase. This gene shows complementary overlapping with the 3-prime region of the TCP1 gene in both mouse and human. These genes are encoded on opposite strands of DNA, as well as in opposite transcriptional orientation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

ACAT2 links:

TCP1 (HGNC:11655): (t-complex 1) The protein encoded by this gene is a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). This complex consists of two identical stacked rings, each containing eight different proteins. Unfolded polypeptides enter the central cavity of the complex and are folded in an ATP-dependent manner. The complex folds various proteins, including actin and tubulin. Alternate transcriptional splice variants of this gene, encoding different isoforms, have been characterized. In addition, three pseudogenes that appear to be derived from this gene have been found. [provided by RefSeq, Jun 2010]

TCP1 links:

Genome browser will be placed here

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, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAT2	NM_005891.3 link	c.1042G>T	p.Ala348Ser	missense_variant	Exon 9 of 9	ENST00000367048.5	NP_005882.2	Q9BWD1-1
TCP1	NM_030752.3 link	c.*368C>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000321394.12	NP_110379.2	P17987
ACAT2	NM_001303253.1 link	c.1129G>T	p.Ala377Ser	missense_variant	Exon 9 of 9		NP_001290182.1	Q9BWD1-2
TCP1	NM_001008897.2 link	c.*368C>A		3_prime_UTR_variant	Exon 11 of 11		NP_001008897.1	E7EQR6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACAT2	ENST00000367048.5 link	c.1042G>T	p.Ala348Ser	missense_variant	Exon 9 of 9	1	NM_005891.3	ENSP00000356015.4	Q9BWD1-1
TCP1	ENST00000321394 link	c.*368C>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_030752.3	ENSP00000317334.7	P17987
ACAT2	ENST00000472052.1 link	n.1272G>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251212

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727234

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:

0.0000710

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1042G>T (p.A348S) alteration is located in exon 9 (coding exon 9) of the ACAT2 gene. This alteration results from a G to T substitution at nucleotide position 1042, causing the alanine (A) at amino acid position 348 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

0.14

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.020

Polyphen

0.99

Vest4

0.78

MVP

0.99

MPC

0.55

ClinPred

0.82

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.74

gMVP

0.86

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

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