16-67000646-A-G

Variant names:

• chr16-67000646-A-G
• rs975996686
• NM_001364782.1:c.269A>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.269A>G​(p.Gln90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Q90P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CES4A NM_001364782.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

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]

ENSG00000289415 (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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CES4A	NM_001364782.1	c.269A>G	p.Gln90Arg	missense_variant	Exon 3 of 14	ENST00000648724.3	NP_001351711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CES4A	ENST00000648724.3	c.269A>G	p.Gln90Arg	missense_variant	Exon 3 of 14		NM_001364782.1	ENSP00000497868.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.49	T;.;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Vest4		0.37
MutPred		0.96		Gain of MoRF binding (P = 0.0652);.;.;
MVP		0.87
MPC		0.69
ClinPred		0.98	D
GERP RS		4.4
gMVP		0.80

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: rs975996686; hg19: chr16-67034549;