Genetic Variant NM_001025195.2:c.431G>T (chr16-55823658-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001025195.2(CES1):c.431G>T(p.Gly144Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G144E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 39)

Failed GnomAD Quality Control

Consequence

CES1
NM_001025195.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.892

Publications

140 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES1	NM_001025195.2 link	c.431G>T	p.Gly144Val	missense_variant	Exon 4 of 14	ENST00000360526.8	NP_001020366.1	P23141-2
CES1	NM_001025194.2 link	c.428G>T	p.Gly143Val	missense_variant	Exon 4 of 14		NP_001020365.1	P23141-1
CES1	NM_001266.5 link	c.428G>T	p.Gly143Val	missense_variant	Exon 4 of 14		NP_001257.4	P23141-3
CES1	XM_005255774.3 link	c.431G>T	p.Gly144Val	missense_variant	Exon 4 of 14		XP_005255831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES1	ENST00000360526.8 link	c.431G>T	p.Gly144Val	missense_variant	Exon 4 of 14	1	NM_001025195.2	ENSP00000353720.4		P23141-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152166

Hom.:

Cov.:

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

GnomAD4 exome

Cov.:

GnomAD4 genome

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

AF:

0.00

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2082

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

.;.;D

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.6

.;H;H

PhyloP100

0.89

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.55

MutPred

0.92

.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.28

MPC

0.23

ClinPred

1.0

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.76

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over