rs3741056

Variant names:

• chr11-108121619-G-C
• rs3741056
• NM_000019.4:c.13G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108121619-G-C
• chr11-108121619-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000019.4(ACAT1):​c.13G>C​(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,550,150 control chromosomes in the GnomAD database, including 84,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7292 hom., cov: 34)
  • Exomes 𝑓: 0.33 (76906 hom.)
• Consequence: ACAT1 NM_000019.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.168
• Publications: 28 publications found

Genes affected

ACAT1 (HGNC:93): (acetyl-CoA acetyltransferase 1) This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Defects in this gene are associated with 3-ketothiolase deficiency, an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and butanone. [provided by RefSeq, Feb 2009]

ACAT1 Gene-Disease associations (from GenCC):

• beta-ketothiolase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ENSG00000255467 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.325577E-4).
• BP6: Variant 11-108121619-G-C is Benign according to our data. Variant chr11-108121619-G-C is described in ClinVar as Benign. ClinVar VariationId is 92295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000019.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	NM_000019.4	MANE Select	c.13G>C	p.Ala5Pro	missense	Exon 1 of 12	NP_000010.1	P24752-1
	ACAT1	NM_001386677.1		c.13G>C	p.Ala5Pro	missense	Exon 1 of 12	NP_001373606.1	A0A5F9ZHL1
	ACAT1	NM_001386678.1		c.13G>C	p.Ala5Pro	missense	Exon 1 of 9	NP_001373607.1	A0A5F9ZI66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAT1	ENST00000265838.9	TSL:1 MANE Select	c.13G>C	p.Ala5Pro	missense	Exon 1 of 12	ENSP00000265838.4	P24752-1
	ACAT1	ENST00000299355.10	TSL:1	c.13G>C	p.Ala5Pro	missense	Exon 1 of 6	ENSP00000299355.6	P24752-2
	ACAT1	ENST00000531813.5	TSL:1	n.13G>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000435965.1	E9PRQ6

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44163 AN: 152138 Hom.: 7292 Cov.: 34

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.366 AC: 55070 AN: 150668 AF XY: 0.371

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.326 AC: 455226 AN: 1397894 Hom.: 76906 Cov.: 39 AF XY: 0.331 AC XY: 228601 AN XY: 689712

African (AFR) AF: 0.141 AC: 4470 AN: 31676

American (AMR) AF: 0.462 AC: 16560 AN: 35826

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 9659 AN: 25164

East Asian (EAS) AF: 0.341 AC: 12217 AN: 35862

South Asian (SAS) AF: 0.482 AC: 38189 AN: 79252

European-Finnish (FIN) AF: 0.312 AC: 14940 AN: 47890

Middle Eastern (MID) AF: 0.453 AC: 2383 AN: 5264

European-Non Finnish (NFE) AF: 0.313 AC: 337401 AN: 1079014

Other (OTH) AF: 0.335 AC: 19407 AN: 57946

GnomAD4 genome AF: 0.290 AC: 44168 AN: 152256 Hom.: 7292 Cov.: 34 AF XY: 0.298 AC XY: 22153 AN XY: 74426

African (AFR) AF: 0.150 AC: 6246 AN: 41566

American (AMR) AF: 0.403 AC: 6163 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3470

East Asian (EAS) AF: 0.346 AC: 1785 AN: 5158

South Asian (SAS) AF: 0.487 AC: 2349 AN: 4826

European-Finnish (FIN) AF: 0.309 AC: 3282 AN: 10610

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21906 AN: 68012

Other (OTH) AF: 0.340 AC: 718 AN: 2114

Alfa AF: 0.320 Hom.: 2606

Bravo AF: 0.289

TwinsUK AF: 0.317 AC: 1174

ALSPAC AF: 0.318 AC: 1224

ESP6500AA AF: 0.122 AC: 498

ESP6500EA AF: 0.254 AC: 2021

ExAC AF: 0.198 AC: 17379

Asia WGS AF: 0.443 AC: 1537 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Deficiency of acetyl-CoA acetyltransferase (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.00083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.17
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.28
Sift	Uncertain	0.015	D
Sift4G	Benign	0.37	T
Polyphen		0.61	P
Vest4		0.22
MPC		0.25
ClinPred		0.0074	T
GERP RS		0.20
PromoterAI		-0.035	Neutral
Varity_R		0.14
gMVP		0.75
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3741056; hg19: chr11-107992346; COSMIC: COSV54919984; COSMIC: COSV54919984;