Genetic Variant CES4A:p.Gln90Arg (chr16-67000646-A-G) – 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_001364782.1(CES4A):c.269A>G(p.Gln90Arg) 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. Q90P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CES4A
NM_001364782.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71

Publications

1 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:

ENSG00000289415 (HGNC:):

ENSG00000289415 links:

Genome browser will be placed here

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, 0.979

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CES4A	NM_001364782.1	MANE Select	c.269A>G	p.Gln90Arg	missense	Exon 3 of 14	NP_001351711.1	Q5XG92-1
CES4A	NM_173815.7		c.269A>G	p.Gln90Arg	missense	Exon 3 of 12	NP_776176.5
CES4A	NM_001190201.2		c.-26A>G		5_prime_UTR	Exon 1 of 12	NP_001177130.1	Q5XG92-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CES4A	ENST00000648724.3	MANE Select	c.269A>G	p.Gln90Arg	missense	Exon 3 of 14	ENSP00000497868.2	Q5XG92-1
CES4A	ENST00000538199.5	TSL:1	c.158A>G	p.Gln53Arg	missense	Exon 2 of 11	ENSP00000441103.1	A0A0C4DGH1
CES4A	ENST00000540579.6	TSL:1	c.-26A>G		5_prime_UTR	Exon 1 of 12	ENSP00000441907.1	Q5XG92-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

4.0

PhyloP100

1.7

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Vest4

0.37

MutPred

0.96

Gain of MoRF binding (P = 0.0652)

MVP

0.87

MPC

0.69

ClinPred

0.98

GERP RS

4.4

PromoterAI

0.040

Neutral

(source)

gMVP

0.80

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over