14-73541556-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001037161.2(ACOT1):​c.521G>C​(p.Arg174Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,133,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 18)
  • Exomes 𝑓: 0.0000018 (1 hom.)
• Consequence: ACOT1 NM_001037161.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

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>C	p.Arg174Pro	missense	Exon 2 of 3	NP_001032238.1	E9KL42
	HEATR4	NM_001220484.1	MANE Select	c.-151-11312C>G		intron	N/A	NP_001207413.1	Q86WZ0
	HEATR4	NM_203309.2		c.-73+17195C>G		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>C	p.Arg174Pro	missense	Exon 2 of 3	ENSP00000311224.4	Q86TX2
	ACOT1	ENST00000557556.1	TSL:1	c.521G>C	p.Arg174Pro	missense	Exon 2 of 3	ENSP00000451764.1	G3V4F2
	HEATR4	ENST00000553558.6	TSL:2 MANE Select	c.-151-11312C>G		intron	N/A	ENSP00000450444.2	Q86WZ0

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1133256 Hom.: 1 Cov.: 30 AF XY: 0.00000354 AC XY: 2 AN XY: 564922

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000226 AC: 2 AN: 884528

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

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.0083	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.7
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.64		Gain of catalytic residue at A179 (P = 1e-04)
MVP		0.80
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.96
Mutation Taster		=68/32	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;