dbSNP rs146595460: CES1:p.Tyr367Phe (chr16-55810997-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001025195.2(CES1):c.1100A>T(p.Tyr367Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. Y367C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CES1
NM_001025195.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.275

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.098049134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES1	NM_001025195.2 link	c.1100A>T	p.Tyr367Phe	missense_variant	Exon 10 of 14	ENST00000360526.8	NP_001020366.1	P23141-2
CES1	NM_001025194.2 link	c.1097A>T	p.Tyr366Phe	missense_variant	Exon 10 of 14		NP_001020365.1	P23141-1
CES1	NM_001266.5 link	c.1094A>T	p.Tyr365Phe	missense_variant	Exon 10 of 14		NP_001257.4	P23141-3
CES1	XM_005255774.3 link	c.1097A>T	p.Tyr366Phe	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.1100A>T	p.Tyr367Phe	missense_variant	Exon 10 of 14	1	NM_001025195.2	ENSP00000353720.4		P23141-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

141580

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249928

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135052

show subpopulations

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 SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

141580

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68422

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.42

DANN

Benign

0.23

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.24

T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.098

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.95

.;.;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.064

Sift

Benign

0.66

T;T;T

Sift4G

Benign

0.75

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.27

MutPred

0.52

.;.;Gain of sheet (P = 0.1208);

MVP

0.25

MPC

0.026

ClinPred

0.026

GERP RS

0.63

Varity_R

0.20

gMVP

0.41

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over