16-67000641-C-G

Variant names:

• chr16-67000641-C-G
• NM_001364782.1:c.264C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001364782.1(CES4A):​c.264C>G​(p.Cys88Trp) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0400

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]

ENSG00000289415 (HGNC:):

ACMG classification

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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES4A	NM_001364782.1	c.264C>G	p.Cys88Trp	missense_variant	Exon 3 of 14	ENST00000648724.3	NP_001351711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES4A	ENST00000648724.3	c.264C>G	p.Cys88Trp	missense_variant	Exon 3 of 14		NM_001364782.1	ENSP00000497868.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.264C>G (p.C88W) alteration is located in exon 3 (coding exon 3) of the CES4A gene. This alteration results from a C to G substitution at nucleotide position 264, causing the cysteine (C) at amino acid position 88 to be replaced by a tryptophan (W). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.48	T;.;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	5.0	H;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-9.3	D;.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Vest4		0.65
MutPred		0.95		Loss of catalytic residue at S92 (P = 0.0447);.;.;
MVP		0.79
MPC		0.84
ClinPred		1.0	D
GERP RS		2.4
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67034544;