NM_001037161.2:c.521G>A

Variant names:

• chr14-73541556-G-A
• rs768462704
• NM_001037161.2:c.521G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001037161.2(ACOT1):​c.521G>A​(p.Arg174Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000723 in 1,244,310 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (1 hom., cov: 18)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: ACOT1 NM_001037161.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

ACOT1 (HGNC:33128): (acyl-CoA thioesterase 1) Enables acyl-CoA hydrolase activity. Involved in acyl-CoA metabolic process; long-chain fatty acid metabolic process; and very long-chain fatty acid metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000299171 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037161.2. 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
	ACOT1	NM_001037161.2	MANE Select	c.521G>A	p.Arg174Gln	missense	Exon 2 of 3	NP_001032238.1	E9KL42
	HEATR4	NM_001220484.1	MANE Select	c.-151-11312C>T		intron	N/A	NP_001207413.1	Q86WZ0
	HEATR4	NM_203309.2		c.-73+17195C>T		intron	N/A	NP_976054.2	Q86WZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOT1	ENST00000311148.9	TSL:1 MANE Select	c.521G>A	p.Arg174Gln	missense	Exon 2 of 3	ENSP00000311224.4	Q86TX2
	ACOT1	ENST00000557556.1	TSL:1	c.521G>A	p.Arg174Gln	missense	Exon 2 of 3	ENSP00000451764.1	G3V4F2
	HEATR4	ENST00000553558.6	TSL:2 MANE Select	c.-151-11312C>T		intron	N/A	ENSP00000450444.2	Q86WZ0

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 110990 Hom.: 1 Cov.: 18

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000541 AC: 1 AN: 184862 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 7 AN: 1133256 Hom.: 1 Cov.: 30 AF XY: 0.00000531 AC XY: 3 AN XY: 564922

African (AFR) AF: 0.0000352 AC: 1 AN: 28418

American (AMR) AF: 0.00 AC: 0 AN: 31646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20202

East Asian (EAS) AF: 0.00 AC: 0 AN: 11522

South Asian (SAS) AF: 0.0000288 AC: 2 AN: 69546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4392

European-Non Finnish (NFE) AF: 0.00000452 AC: 4 AN: 884528

Other (OTH) AF: 0.00 AC: 0 AN: 46000

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111054 Hom.: 1 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 53080

African (AFR) AF: 0.00 AC: 0 AN: 33018

American (AMR) AF: 0.000204 AC: 2 AN: 9820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2676

East Asian (EAS) AF: 0.00 AC: 0 AN: 1388

South Asian (SAS) AF: 0.00 AC: 0 AN: 3346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51936

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000102 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.7
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.58		Gain of catalytic residue at A179 (P = 3e-04)
MVP		0.70
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.57
gMVP		0.84
Mutation Taster		=89/11	polymorphism

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: rs768462704; hg19: chr14-74008260; COSMIC: COSV58572097; COSMIC: COSV58572097;