chr16-66963308-G-T

Variant names:

• chr16-66963308-G-T
• rs1490080959
• NM_024922.6:c.212G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024922.6(CES3):​c.212G>T​(p.Gly71Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G71D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CES3 NM_024922.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.76
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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.212G>T	p.Gly71Val	missense	Exon 2 of 13	NP_079198.2
	CES3	NM_001185177.2		c.212G>T	p.Gly71Val	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.212G>T	p.Gly71Val	missense	Exon 2 of 13	ENSP00000304782.4	Q6UWW8-1
	CES3	ENST00000394037.5	TSL:1	c.212G>T	p.Gly71Val	missense	Exon 2 of 13	ENSP00000377602.1	A0A0C4DFY7
	CES3	ENST00000885488.1		c.212G>T	p.Gly71Val	missense	Exon 2 of 12	ENSP00000555547.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250688 AF XY: 0.00

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461518 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727084

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

American (AMR) AF: 0.00 AC: 0 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: 53050

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		8.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.98		Loss of disorder (P = 0.0511)
MVP		0.83
MPC		0.68
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.91

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: rs1490080959; hg19: chr16-66997211;