Genetic Variant CES1:p.Tyr387Cys (chr16-55810937-T-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001025195.2(CES1):c.1160A>G(p.Tyr387Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CES1
NM_001025195.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.266

Variant links:

Genes affected

CES1 (HGNC:1863): (carboxylesterase 1) This gene encodes a member of the carboxylesterase large family. The family members are responsible for the hydrolysis or transesterification of various xenobiotics, such as cocaine and heroin, and endogenous substrates with ester, thioester, or amide bonds. They may participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This enzyme is the major liver enzyme and functions in liver drug clearance. Mutations of this gene cause carboxylesterase 1 deficiency. Three transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

CES1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3009528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES1	NM_001025195.2 link	c.1160A>G	p.Tyr387Cys	missense_variant	Exon 10 of 14	ENST00000360526.8	NP_001020366.1	P23141-2
CES1	NM_001025194.2 link	c.1157A>G	p.Tyr386Cys	missense_variant	Exon 10 of 14		NP_001020365.1	P23141-1
CES1	NM_001266.5 link	c.1154A>G	p.Tyr385Cys	missense_variant	Exon 10 of 14		NP_001257.4	P23141-3
CES1	XM_005255774.3 link	c.1157A>G	p.Tyr386Cys	missense_variant	Exon 10 of 14		XP_005255831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES1	ENST00000360526.8 link	c.1160A>G	p.Tyr387Cys	missense_variant	Exon 10 of 14	1	NM_001025195.2	ENSP00000353720.4		P23141-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251168

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461384

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1157A>G (p.Y386C) alteration is located in exon 10 (coding exon 10) of the CES1 gene. This alteration results from a A to G substitution at nucleotide position 1157, causing the tyrosine (Y) at amino acid position 386 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Uncertain

0.52

.;.;D

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

.;.;M

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.064

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.017

B;.;B

Vest4

0.48

MutPred

0.65

.;.;Gain of ubiquitination at K384 (P = 0.1245);

MVP

0.27

MPC

0.031

ClinPred

0.38

GERP RS

-0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.50

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