Genetic Variant CES4A:p.Pro85Gln (chr16-66995823-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001364782.1(CES4A):c.254C>A(p.Pro85Gln) 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 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 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. P85L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CES4A
NM_001364782.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.46

Publications

0 publications found

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]

CES4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364782.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES4A	NM_001364782.1	MANE Select	c.254C>A	p.Pro85Gln	missense	Exon 2 of 14	NP_001351711.1	Q5XG92-1
	CES4A	NM_173815.7		c.254C>A	p.Pro85Gln	missense	Exon 2 of 12	NP_776176.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CES4A	ENST00000648724.3	MANE Select	c.254C>A	p.Pro85Gln	missense	Exon 2 of 14	ENSP00000497868.2	Q5XG92-1
CES4A	ENST00000538199.5	TSL:1	c.143C>A	p.Pro48Gln	missense	Exon 1 of 11	ENSP00000441103.1	A0A0C4DGH1
CES4A	ENST00000862247.1		c.254C>A	p.Pro85Gln	missense	Exon 2 of 15	ENSP00000532306.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461128

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111944

Other (OTH)

AF:

0.00

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

0.045

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.7

PhyloP100

3.5

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-6.6

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.36

MutPred

0.59

Loss of glycosylation at P86 (P = 0.0679)

MVP

0.72

MPC

0.62

ClinPred

0.84

GERP RS

4.0

PromoterAI

0.0060

Neutral

(source)

gMVP

0.56

Mutation Taster

=92/8

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over