16-66995643-A-G

Position:

• chr16-66995643-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001364782.1(CES4A):​c.74A>G​(p.Lys25Arg) 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 benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.786

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098650485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CES4A	NM_001364782.1	c.74A>G	p.Lys25Arg	missense_variant	2/14	ENST00000648724.3	NP_001351711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CES4A	ENST00000648724.3	c.74A>G	p.Lys25Arg	missense_variant	2/14		NM_001364782.1	ENSP00000497868	P1
CES4A	ENST00000540947.6	c.74A>G	p.Lys25Arg	missense_variant	2/12	2		ENSP00000444052
CES4A	ENST00000567587.6	c.17A>G	p.Lys6Arg	missense_variant, NMD_transcript_variant	1/11	5		ENSP00000458664
CES4A	ENST00000538199.5			upstream_gene_variant		1		ENSP00000441103

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.74A>G (p.K25R) alteration is located in exon 2 (coding exon 2) of the CES4A gene. This alteration results from a A to G substitution at nucleotide position 74, causing the lysine (K) at amino acid position 25 to be replaced by an arginine (R). 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	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.7
DANN	Benign	0.93
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.37	T;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.80	N;.
REVEL	Benign	0.055
Sift	Benign	0.078	T;.
Sift4G	Benign	0.24	T;.
Vest4		0.24
MutPred		0.34		.;Loss of methylation at K48 (P = 0.0517);
MVP		0.67
MPC		0.29
ClinPred		0.18	T
GERP RS		0.83
gMVP		0.15

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

Other links and lift over

dbSNP: rs1425871533; hg19: chr16-67029546;