chr16-66995747-C-G

Variant names:

• chr16-66995747-C-G
• rs772475063
• NM_001364782.1:c.178C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001364782.1(CES4A):​c.178C>G​(p.Pro60Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000568 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30
• Publications: 0 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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

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.178C>G	p.Pro60Ala	missense	Exon 2 of 14	NP_001351711.1	Q5XG92-1
	CES4A	NM_173815.7		c.178C>G	p.Pro60Ala	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.178C>G	p.Pro60Ala	missense	Exon 2 of 14	ENSP00000497868.2	Q5XG92-1
	CES4A	ENST00000538199.5	TSL:1	c.67C>G	p.Pro23Ala	missense	Exon 1 of 11	ENSP00000441103.1	A0A0C4DGH1
	CES4A	ENST00000862247.1		c.178C>G	p.Pro60Ala	missense	Exon 2 of 15	ENSP00000532306.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000801 AC: 20 AN: 249574 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000568 AC: 83 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54 AN XY: 727242

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86258

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000993 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	Uncertain	0.47
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		6.3
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.45
MutPred		0.95		Loss of catalytic residue at P59 (P = 0.0096)
MVP		0.81
MPC		0.71
ClinPred		0.88	D
GERP RS		4.9
PromoterAI		0.0022	Neutral
gMVP		0.67
Mutation Taster		=44/56	disease causing

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: rs772475063; hg19: chr16-67029650;