16-66963910-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024922.6(CES3):​c.535C>A​(p.Arg179Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R179C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CES3
NM_024922.6 missense

Scores

6
10
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68
Variant links:
Genes affected
CES3 (HGNC:1865): (carboxylesterase 3) 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 gene is expressed in several tissues, particularly in colon, trachea and in brain, and the protein participates in colon and neural drug metabolism. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported, but the biological validity and/or full-length nature of some variants have not been determined.[provided by RefSeq, Jun 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CES3NM_024922.6 linkc.535C>A p.Arg179Ser missense_variant Exon 4 of 13 ENST00000303334.9 NP_079198.2 Q6UWW8-1
CES3NM_001185177.2 linkc.535C>A p.Arg179Ser missense_variant Exon 4 of 13 NP_001172106.1 Q6UWW8A0A0C4DFY7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CES3ENST00000303334.9 linkc.535C>A p.Arg179Ser missense_variant Exon 4 of 13 1 NM_024922.6 ENSP00000304782.4 Q6UWW8-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251392
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135858
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461136
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726734
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.012
T
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Pathogenic
4.5
H;.
PrimateAI
Benign
0.30
T
PROVEAN
Pathogenic
-5.4
D;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.79
MutPred
0.93
Loss of methylation at R179 (P = 0.0272);Loss of methylation at R179 (P = 0.0272);
MVP
0.85
MPC
0.63
ClinPred
0.99
D
GERP RS
2.0
Varity_R
0.56
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs148620443; hg19: chr16-66997813; COSMIC: COSV57593639; COSMIC: COSV57593639; API