16-55810997-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001025195.2(CES1):c.1100A>G(p.Tyr367Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,602,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: CES1 NM_001025195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.275

Genes affected

CES1 (HGNC:1863): (carboxylesterase 1) 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 enzyme is the major liver enzyme and functions in liver drug clearance. Mutations of this gene cause carboxylesterase 1 deficiency. Three transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067707956).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000639 (933/1460408) while in subpopulation MID AF= 0.0232 (133/5740). AF 95% confidence interval is 0.02. There are 0 homozygotes in gnomad4_exome. There are 497 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CES1	NM_001025195.2	c.1100A>G	p.Tyr367Cys	missense_variant	10/14	ENST00000360526.8
CES1	NM_001025194.2	c.1097A>G	p.Tyr366Cys	missense_variant	10/14
CES1	NM_001266.5	c.1094A>G	p.Tyr365Cys	missense_variant	10/14
CES1	XM_005255774.3	c.1097A>G	p.Tyr366Cys	missense_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CES1	ENST00000360526.8	c.1100A>G	p.Tyr367Cys	missense_variant	10/14	1	NM_001025195.2	P4

Frequencies

GnomAD3 genomes AF: 0.000735 AC: 104 AN: 141570 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00176

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.000993

Gnomad OTH AF: 0.00212

GnomAD3 exomes AF: 0.000804 AC: 201 AN: 249928 Hom.: 0 AF XY: 0.000822 AC XY: 111 AN XY: 135052

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000699

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.000639 AC: 933 AN: 1460408 Hom.: 0 Cov.: 33 AF XY: 0.000684 AC XY: 497 AN XY: 726524

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000472

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.000734 AC: 104 AN: 141682 Hom.: 0 Cov.: 34 AF XY: 0.000715 AC XY: 49 AN XY: 68536

Gnomad4 AFR AF: 0.000188

Gnomad4 AMR AF: 0.000953

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00176

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000993

Gnomad4 OTH AF: 0.00210

Alfa AF: 0.00104 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000840 AC: 102

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00143

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1097A>G (p.Y366C) alteration is located in exon 10 (coding exon 10) of the CES1 gene. This alteration results from a A to G substitution at nucleotide position 1097, causing the tyrosine (Y) at amino acid position 366 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	12
Dann	Benign	0.56
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.31	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.091	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.073	B;.;B
Vest4		0.62
MVP		0.35
MPC		0.19
ClinPred		0.029	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs146595460; hg19: chr16-55844909;