14-73537686-C-T

Position:

chr14-73537686-C-T

Variant summary

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

The ENST00000311148.9(ACOT1):c.265C>T(p.Pro89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,248,094 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P89P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00080 ( 29 hom., cov: 19)

Exomes 𝑓: 0.0011 ( 340 hom. )

Consequence

ACOT1
ENST00000311148.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.72

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=0.0175803).

BP6

Variant 14-73537686-C-T is Benign according to our data. Variant chr14-73537686-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2357026.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr14-73537686-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOT1	NM_001037161.2 linkuse as main transcript	c.265C>T	p.Pro89Ser	missense_variant	1/3	ENST00000311148.9	NP_001032238.1
HEATR4	NM_001220484.1 linkuse as main transcript	c.-151-7442G>A		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.265C>T	p.Pro89Ser	missense_variant	1/3	1	NM_001037161.2	ENSP00000311224	P1
HEATR4	ENST00000553558.6 linkuse as main transcript	c.-151-7442G>A		intron_variant		2	NM_001220484.1	ENSP00000450444	P1

Frequencies

GnomAD3 genomes

AF:

0.000798

AC:

AN:

117780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000412

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00139

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:

0.00118

Gnomad OTH

AF:

0.000633

GnomAD3 exomes

AF:

0.000897

AC:

145

AN:

161716

Hom.:

AF XY:

0.000854

AC XY:

AN XY:

90146

show subpopulations

Gnomad AFR exome

AF:

0.0000923

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000429

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.00108

AC:

1222

AN:

1130252

Hom.:

340

Cov.:

AF XY:

0.00106

AC XY:

594

AN XY:

563012

show subpopulations

Gnomad4 AFR exome

AF:

0.000139

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000376

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.00100

GnomAD4 genome

AF:

0.000798

AC:

AN:

117842

Hom.:

Cov.:

AF XY:

0.000722

AC XY:

AN XY:

56800

show subpopulations

Gnomad4 AFR

AF:

0.000411

Gnomad4 AMR

AF:

0.00139

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.000624

Alfa

AF:

0.000981

Hom.:

ExAC

AF:

0.000725

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

Jan 09, 2024

The c.265C>T (p.P89S) alteration is located in exon 1 (coding exon 1) of the ACOT1 gene. This alteration results from a C to T substitution at nucleotide position 265, causing the proline (P) at amino acid position 89 to be replaced by a serine (S). 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, 2023

ACOT1: BP4, BS2; HEATR4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

0.013

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

N;N;D;D;D

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0090

D;T

Sift4G

Benign

0.075

T;T

Polyphen

0.96

D;.

Vest4

0.19

MVP

0.86

ClinPred

0.10

GERP RS

3.6

Varity_R

0.15

gMVP

0.49

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

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