14-73537804-A-G

Position:

chr14-73537804-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000311148.9(ACOT1):c.383A>G(p.Tyr128Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,218,114 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y128D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 41 hom., cov: 19)

Exomes 𝑓: 0.0016 ( 511 hom. )

Consequence

ACOT1
ENST00000311148.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.195

Variant links:

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]

ACOT1 links:

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

HEATR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017419428).

BP6

Variant 14-73537804-A-G is Benign according to our data. Variant chr14-73537804-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2352562.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr14-73537804-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOT1	NM_001037161.2 linkuse as main transcript	c.383A>G	p.Tyr128Cys	missense_variant	1/3	ENST00000311148.9	NP_001032238.1
HEATR4	NM_001220484.1 linkuse as main transcript	c.-151-7560T>C		intron_variant		ENST00000553558.6	NP_001207413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACOT1	ENST00000311148.9 linkuse as main transcript	c.383A>G	p.Tyr128Cys	missense_variant	1/3	1	NM_001037161.2	ENSP00000311224	P1
HEATR4	ENST00000553558.6 linkuse as main transcript	c.-151-7560T>C		intron_variant		2	NM_001220484.1	ENSP00000450444	P1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

120

AN:

115866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

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:

0.00169

Gnomad OTH

AF:

0.00130

GnomAD3 exomes

AF:

0.000789

AC:

AN:

117912

Hom.:

AF XY:

0.000754

AC XY:

AN XY:

66316

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.000768

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:

0.00143

Gnomad OTH exome

AF:

0.000303

GnomAD4 exome

AF:

0.00157

AC:

1733

AN:

1102184

Hom.:

511

Cov.:

AF XY:

0.00147

AC XY:

803

AN XY:

546932

show subpopulations

Gnomad4 AFR exome

AF:

0.0000359

Gnomad4 AMR exome

AF:

0.000979

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000196

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000104

Gnomad4 NFE exome

AF:

0.00188

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.00104

AC:

120

AN:

115930

Hom.:

Cov.:

AF XY:

0.000933

AC XY:

AN XY:

55760

show subpopulations

Gnomad4 AFR

AF:

0.000364

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00169

Gnomad4 OTH

AF:

0.00128

Alfa

AF:

0.000274

Hom.:

ExAC

AF:

0.000786

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.383A>G (p.Y128C) alteration is located in exon 1 (coding exon 1) of the ACOT1 gene. This alteration results from a A to G substitution at nucleotide position 383, causing the tyrosine (Y) at amino acid position 128 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

ACOT1: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.3

DANN

Benign

0.77

DEOGEN2

Benign

0.037

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.21

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.074

Sift

Benign

0.17

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0010

B;.

Vest4

0.053

MVP

0.55

ClinPred

0.016

GERP RS

-0.063

Varity_R

0.11

gMVP

0.67

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