16-66995823-C-T

Variant names:

• chr16-66995823-C-T
• rs376340766
• NM_001364782.1:c.254C>T

Variant summary

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

The NM_001364782.1(CES4A):​c.254C>T​(p.Pro85Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES4A	NM_001364782.1	MANE Select	c.254C>T	p.Pro85Leu	missense	Exon 2 of 14	NP_001351711.1	Q5XG92-1
	CES4A	NM_173815.7		c.254C>T	p.Pro85Leu	missense	Exon 2 of 12	NP_776176.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES4A	ENST00000648724.3	MANE Select	c.254C>T	p.Pro85Leu	missense	Exon 2 of 14	ENSP00000497868.2	Q5XG92-1
	CES4A	ENST00000538199.5	TSL:1	c.143C>T	p.Pro48Leu	missense	Exon 1 of 11	ENSP00000441103.1	A0A0C4DGH1
	CES4A	ENST00000862247.1		c.254C>T	p.Pro85Leu	missense	Exon 2 of 15	ENSP00000532306.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249246 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000767 AC: 112 AN: 1461128 Hom.: 0 Cov.: 31 AF XY: 0.0000702 AC XY: 51 AN XY: 726858

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000671 AC: 3 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111944

Other (OTH) AF: 0.000182 AC: 11 AN: 60318

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000414 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.33
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.5
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Benign	0.26
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.36
MutPred		0.65		Loss of catalytic residue at P85 (P = 0.0266)
MVP		0.68
MPC		0.41
ClinPred		0.90	D
GERP RS		4.0
PromoterAI		-0.024	Neutral
gMVP		0.59
Mutation Taster		=95/5	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: rs376340766; hg19: chr16-67029726;