16-67000957-T-G

Position:

• chr16-67000957-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001364782.1(CES4A):​c.503T>G​(p.Leu168Arg) 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 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

Genes affected

CES4A (HGNC:26741): (carboxylesterase 4A) 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 also participate in fatty acyl and cholesterol ester metabolism, and may play a role in the blood-brain barrier system. This gene, also called CES6, encodes a secreted enzyme, and may play a role in the detoxification of drugs and xenobiotics in neural and other tissues of the body and in the cerebrospinal fluid. Multiple transcript variants encoding different isoforms have been reported, but the full-length nature and/or biological validity of some variants have not been determined. [provided by RefSeq, Jun 2010]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CES4A	NM_001364782.1	c.503T>G	p.Leu168Arg	missense_variant	4/14	ENST00000648724.3	NP_001351711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CES4A	ENST00000648724.3	c.503T>G	p.Leu168Arg	missense_variant	4/14		NM_001364782.1	ENSP00000497868	P1
	ENST00000685903.1	n.88A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

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

Feb 05, 2024

The c.503T>G (p.L168R) alteration is located in exon 4 (coding exon 4) of the CES4A gene. This alteration results from a T to G substitution at nucleotide position 503, causing the leucine (L) at amino acid position 168 to be replaced by an arginine (R). 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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.85	D;.;T;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.
MutationTaster	Benign	0.57	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D;.;D;D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.88
MutPred		0.88		Gain of methylation at L168 (P = 0.0287);.;.;.;.;
MVP		0.73
MPC		0.48
ClinPred		0.97	D
GERP RS		3.8
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs764378038; hg19: chr16-67034860;