16-66963187-G-A

Variant names:

• chr16-66963187-G-A
• rs753138233
• NM_024922.6:c.91G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024922.6(CES3):​c.91G>A​(p.Val31Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CES3 NM_024922.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.167
• Publications: 0 publications found

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]

ENSG00000265408 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07085958).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024922.6. 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
	CES3	NM_024922.6	MANE Select	c.91G>A	p.Val31Ile	missense	Exon 2 of 13	NP_079198.2
	CES3	NM_001185177.2		c.91G>A	p.Val31Ile	missense	Exon 2 of 13	NP_001172106.1	A0A0C4DFY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES3	ENST00000303334.9	TSL:1 MANE Select	c.91G>A	p.Val31Ile	missense	Exon 2 of 13	ENSP00000304782.4	Q6UWW8-1
	CES3	ENST00000394037.5	TSL:1	c.91G>A	p.Val31Ile	missense	Exon 2 of 13	ENSP00000377602.1	A0A0C4DFY7
	CES3	ENST00000885488.1		c.91G>A	p.Val31Ile	missense	Exon 2 of 12	ENSP00000555547.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251372 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.41
DANN	Benign	0.91
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.17
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.063
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.0060	B
Vest4		0.12
MutPred		0.40		Loss of disorder (P = 0.1212)
MVP		0.24
MPC		0.11
ClinPred		0.025	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs753138233; hg19: chr16-66997090;