rs772475063

Variant summary

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

The NM_001364782.1(CES4A):ā€‹c.178C>Gā€‹(p.Pro60Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000568 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000057 ( 0 hom. )

Consequence

CES4A
NM_001364782.1 missense

Scores

7
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30
Variant links:
Genes affected
CES4A (HGNC:26741): (carboxylesterase 4A) 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 also participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This gene, also called CES6, encodes a secreted enzyme, and may play a role in the detoxification of drugs and xenobiotics in neural and other tissues of the body and in the cerebrospinal fluid. Multiple transcript variants encoding different isoforms have been reported, but the full-length nature and/or biological validity 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, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CES4ANM_001364782.1 linkc.178C>G p.Pro60Ala missense_variant Exon 2 of 14 ENST00000648724.3 NP_001351711.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CES4AENST00000648724.3 linkc.178C>G p.Pro60Ala missense_variant Exon 2 of 14 NM_001364782.1 ENSP00000497868.2 Q5XG92-1
CES4AENST00000538199.5 linkc.67C>G p.Pro23Ala missense_variant Exon 1 of 11 1 ENSP00000441103.1 A0A0C4DGH1
CES4AENST00000540947.6 linkc.178C>G p.Pro60Ala missense_variant Exon 2 of 12 2 ENSP00000444052.2 Q5XG92-5
CES4AENST00000567587.6 linkn.118C>G non_coding_transcript_exon_variant Exon 1 of 11 5 ENSP00000458664.2 I3L191

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000801
AC:
20
AN:
249574
Hom.:
0
AF XY:
0.000126
AC XY:
17
AN XY:
135402
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:
0.000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000568
AC:
83
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.0000743
AC XY:
54
AN XY:
727242
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:
0.000927
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000993
AC:
12
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 16, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.178C>G (p.P60A) alteration is located in exon 2 (coding exon 2) of the CES4A gene. This alteration results from a C to G substitution at nucleotide position 178, causing the proline (P) at amino acid position 60 to be replaced by an alanine (A). 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
Uncertain
0.47
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Uncertain
0.10
CADD
Benign
22
DANN
Uncertain
0.98
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;.;D
M_CAP
Benign
0.051
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
4.2
H;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Pathogenic
-7.1
D;.;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0
D;.;D
Vest4
0.45
MutPred
0.95
Loss of catalytic residue at P59 (P = 0.0096);.;.;
MVP
0.81
MPC
0.71
ClinPred
0.88
D
GERP RS
4.9
gMVP
0.67

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.

Other links and lift over

dbSNP: rs772475063; hg19: chr16-67029650; API