chr16-66988822-C-T

Variant names:

• chr16-66988822-C-T
• rs539063507
• NM_001364782.1:c.50C>T

Variant summary

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

The NM_001364782.1(CES4A):​c.50C>T​(p.Thr17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,566,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.299
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23488864).

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.50C>T	p.Thr17Met	missense	Exon 1 of 14	NP_001351711.1	Q5XG92-1
	CES4A	NM_173815.7		c.50C>T	p.Thr17Met	missense	Exon 1 of 12	NP_776176.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES4A	ENST00000648724.3	MANE Select	c.50C>T	p.Thr17Met	missense	Exon 1 of 14	ENSP00000497868.2	Q5XG92-1
	CES4A	ENST00000862247.1		c.50C>T	p.Thr17Met	missense	Exon 1 of 15	ENSP00000532306.1
	CES4A	ENST00000862245.1		c.50C>T	p.Thr17Met	missense	Exon 1 of 15	ENSP00000532304.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000339 AC: 6 AN: 177250 AF XY: 0.0000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000354

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000413

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000141 AC: 20 AN: 1414442 Hom.: 0 Cov.: 30 AF XY: 0.00000715 AC XY: 5 AN XY: 699436

African (AFR) AF: 0.00 AC: 0 AN: 32008

American (AMR) AF: 0.0000254 AC: 1 AN: 39394

Ashkenazi Jewish (ASJ) AF: 0.0000789 AC: 2 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 36692

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49848

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5438

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1086798

Other (OTH) AF: 0.0000342 AC: 2 AN: 58528

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74494

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000170 AC: 2

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	0.099
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.96
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.30
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.11
Sift	Benign	0.25	T
Sift4G	Benign	0.14	T
Vest4		0.14
MutPred		0.69		Gain of stability (P = 0.1318)
MVP		0.71
MPC		0.21
ClinPred		0.13	T
GERP RS		2.5
PromoterAI		-0.041	Neutral
gMVP		0.24
Mutation Taster		=90/10	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: rs539063507; hg19: chr16-67022725; COSMIC: COSV100110391;