16-66963881-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024922.6(CES3):c.506G>A(p.Gly169Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,614,198 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: CES3 NM_024922.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

Genes affected

CES3 (HGNC:1865): (carboxylesterase 3) 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 may participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This gene is expressed in several tissues, particularly in colon, trachea and in brain, and the protein participates in colon and neural drug metabolism. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported, but the biological validity and/or full-length nature of some variants have not been determined.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005900353).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CES3	NM_024922.6	c.506G>A	p.Gly169Glu	missense_variant	4/13	ENST00000303334.9
CES3	NM_001185177.2	c.506G>A	p.Gly169Glu	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CES3	ENST00000303334.9	c.506G>A	p.Gly169Glu	missense_variant	4/13	1	NM_024922.6	P3
CES3	ENST00000394037.5	c.506G>A	p.Gly169Glu	missense_variant	4/13	1		A2
CES3	ENST00000570236.1	c.506G>A	p.Gly169Glu	missense_variant, NMD_transcript_variant	4/11	5
CES3	ENST00000566453.1	c.*402G>A		3_prime_UTR_variant, NMD_transcript_variant	5/7	3

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152226 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000322 AC: 81 AN: 251462 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135902

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000432 AC: 632 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.000414 AC XY: 301 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152344 Hom.: 2 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74498

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000590 Hom.: 0

Bravo AF: 0.000895

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000593

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

Oct 26, 2021

The c.506G>A (p.G169E) alteration is located in exon 4 (coding exon 4) of the CES3 gene. This alteration results from a G to A substitution at nucleotide position 506, causing the glycine (G) at amino acid position 169 to be replaced by a glutamic acid (E). 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	0.51
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.1
Dann	Benign	0.72
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.040	N;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MVP		0.38
MPC		0.22
ClinPred		0.0027	T
GERP RS		1.1
Varity_R		0.034
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs143859743; hg19: chr16-66997784;