rs767343447

Variant names:

• chr16-55819548-G-A
• rs767343447
• NM_001025195.2:c.893C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001025195.2(CES1):​c.893C>T​(p.Thr298Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CES1 NM_001025195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.16
• Publications: 6 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27488256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025195.2. 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
	CES1	NM_001025195.2	MANE Select	c.893C>T	p.Thr298Met	missense	Exon 7 of 14	NP_001020366.1	P23141-2
	CES1	NM_001025194.2		c.890C>T	p.Thr297Met	missense	Exon 7 of 14	NP_001020365.1	P23141-1
	CES1	NM_001266.5		c.890C>T	p.Thr297Met	missense	Exon 7 of 14	NP_001257.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CES1	ENST00000360526.8	TSL:1 MANE Select	c.893C>T	p.Thr298Met	missense	Exon 7 of 14	ENSP00000353720.4	P23141-2
	CES1	ENST00000361503.8	TSL:1	c.890C>T	p.Thr297Met	missense	Exon 7 of 14	ENSP00000355193.4	P23141-1
	CES1	ENST00000422046.6	TSL:1	c.890C>T	p.Thr297Met	missense	Exon 7 of 14	ENSP00000390492.2	P23141-3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251338 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461118 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 726920

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000598 AC: 2 AN: 33452

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111412

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000845735), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

African (AFR) AF: 0.000145 AC: 6 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000828 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.049	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.33
MVP		0.51
MPC		0.15
ClinPred		0.15	T
GERP RS		-5.5
Varity_R		0.15
gMVP		0.49
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: rs767343447; hg19: chr16-55853460; COSMIC: COSV62085843; COSMIC: COSV62085843;