16-55812976-G-T

Variant names:

• chr16-55812976-G-T
• rs773189319
• NM_001025195.2:c.1013C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001025195.2(CES1):​c.1013C>A​(p.Ala338Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/22 in silico tools predict a benign 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. A338G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CES1 NM_001025195.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1013C>A	p.Ala338Asp	missense	Exon 9 of 14	NP_001020366.1	P23141-2
	CES1	NM_001025194.2		c.1010C>A	p.Ala337Asp	missense	Exon 9 of 14	NP_001020365.1	P23141-1
	CES1	NM_001266.5		c.1010C>A	p.Ala337Asp	missense	Exon 9 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.1013C>A	p.Ala338Asp	missense	Exon 9 of 14	ENSP00000353720.4	P23141-2
	CES1	ENST00000361503.8	TSL:1	c.1010C>A	p.Ala337Asp	missense	Exon 9 of 14	ENSP00000355193.4	P23141-1
	CES1	ENST00000422046.6	TSL:1	c.1010C>A	p.Ala337Asp	missense	Exon 9 of 14	ENSP00000390492.2	P23141-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461764 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727184

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ 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 Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.9
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.20
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.12	B
Vest4		0.55
MutPred		0.41		Gain of disorder (P = 0.0725)
MVP		0.50
MPC		0.12
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.60
gMVP		0.39

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: rs773189319; hg19: chr16-55846888;