rs12149373

Variant names:

• chr16-55833101-T-C
• rs12149373
• ENST00000361503.8:c.-46A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000361503.8(CES1):​c.-46A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 126,536 control chromosomes in the GnomAD database, including 2,198 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (2198 hom., cov: 32)
  • Exomes 𝑓: 0.019 (4720 hom.)
  • Failed GnomAD Quality Control
• Consequence: CES1 ENST00000361503.8 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 10 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAd4 at 2198 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES1	NM_001025195.2	c.-46A>G		upstream_gene_variant		ENST00000360526.8	NP_001020366.1
CES1	NM_001025194.2	c.-46A>G		upstream_gene_variant			NP_001020365.1
CES1	NM_001266.5	c.-46A>G		upstream_gene_variant			NP_001257.4
CES1	XM_005255774.3	c.-46A>G		upstream_gene_variant			XP_005255831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES1	ENST00000360526.8	c.-46A>G		upstream_gene_variant		1	NM_001025195.2	ENSP00000353720.4

Frequencies

GnomAD3 genomes AF: 0.199 AC: 25218 AN: 126442 Hom.: 2200 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.0262 AC: 5391 AN: 205956 AF XY: 0.0242

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0754

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0288

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0189 AC: 22064 AN: 1168146 Hom.: 4720 Cov.: 26 AF XY: 0.0204 AC XY: 11885 AN XY: 581594

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

African (AFR) AF: 0.0269 AC: 741 AN: 27508

American (AMR) AF: 0.0152 AC: 599 AN: 39284

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 461 AN: 21992

East Asian (EAS) AF: 0.0635 AC: 1754 AN: 27642

South Asian (SAS) AF: 0.0378 AC: 2562 AN: 67864

European-Finnish (FIN) AF: 0.0435 AC: 1836 AN: 42198

Middle Eastern (MID) AF: 0.0524 AC: 223 AN: 4254

European-Non Finnish (NFE) AF: 0.0142 AC: 12662 AN: 889204

Other (OTH) AF: 0.0254 AC: 1226 AN: 48200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.199 AC: 25222 AN: 126536 Hom.: 2198 Cov.: 32 AF XY: 0.199 AC XY: 12244 AN XY: 61584

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

African (AFR) AF: 0.179 AC: 6532 AN: 36582

American (AMR) AF: 0.188 AC: 2276 AN: 12096

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 503 AN: 2922

East Asian (EAS) AF: 0.340 AC: 1322 AN: 3888

South Asian (SAS) AF: 0.225 AC: 859 AN: 3814

European-Finnish (FIN) AF: 0.192 AC: 1691 AN: 8818

Middle Eastern (MID) AF: 0.325 AC: 78 AN: 240

European-Non Finnish (NFE) AF: 0.207 AC: 11516 AN: 55756

Other (OTH) AF: 0.213 AC: 375 AN: 1760

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.169 Hom.: 375

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.33
PhyloP100		-1.1
PromoterAI		0.029	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs12149373; hg19: chr16-55867013; COSMIC: COSV62085674; COSMIC: COSV62085674;