11-108121579-T-A

Position:

• chr11-108121579-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000019.4(ACAT1):​c.-28T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,549,206 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: ACAT1 NM_000019.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.420

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-108121579-T-A is Benign according to our data. Variant chr11-108121579-T-A is described in ClinVar as [Benign]. Clinvar id is 302194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00277 (422/152362) while in subpopulation EAS AF= 0.029 (150/5174). AF 95% confidence interval is 0.0252. There are 5 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAT1	NM_000019.4	c.-28T>A		5_prime_UTR_variant	1/12	ENST00000265838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAT1	ENST00000265838.9	c.-28T>A		5_prime_UTR_variant	1/12	1	NM_000019.4	P1
	ENST00000525548.1	n.106A>T		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00297 AC: 446 AN: 150194 Hom.: 7 AF XY: 0.00262 AC XY: 210 AN XY: 80218

Gnomad AFR exome AF: 0.00635

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0337

Gnomad SAS exome AF: 0.000308

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00324

GnomAD4 exome AF: 0.000998 AC: 1394 AN: 1396844 Hom.: 19 Cov.: 29 AF XY: 0.000935 AC XY: 644 AN XY: 689030

Gnomad4 AFR exome AF: 0.00545

Gnomad4 AMR exome AF: 0.000392

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0273

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000232

Gnomad4 OTH exome AF: 0.00304

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74506

Gnomad4 AFR AF: 0.00594

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0290

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.00311

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of acetyl-CoA acetyltransferase Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.75
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs36216231; hg19: chr11-107992306;