13-46777529-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001984.2(ESD):c.695G>C(p.Gly232Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESD NM_001984.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

Genes affected

ESD (HGNC:3465): (esterase D) This gene encodes a serine hydrolase that belongs to the esterase D family. The encoded enzyme is active toward numerous substrates including O-acetylated sialic acids, and it may be involved in the recycling of sialic acids. This gene is used as a genetic marker for retinoblastoma and Wilson's disease. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31190997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESD	NM_001984.2	c.695G>C	p.Gly232Ala	missense_variant	9/10	ENST00000378720.8
ESD	XM_005266278.4	c.695G>C	p.Gly232Ala	missense_variant	9/10
ESD	XM_011534954.2	c.695G>C	p.Gly232Ala	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESD	ENST00000378720.8	c.695G>C	p.Gly232Ala	missense_variant	9/10	1	NM_001984.2	P1
ESD	ENST00000471867.3	c.695G>C	p.Gly232Ala	missense_variant	9/9	2
ESD	ENST00000378697.5	c.608G>C	p.Gly203Ala	missense_variant	10/11	5
ESD	ENST00000412582.5	c.539G>C	p.Gly180Ala	missense_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250504 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 13, 2022

The c.695G>C (p.G232A) alteration is located in exon 9 (coding exon 7) of the ESD gene. This alteration results from a G to C substitution at nucleotide position 695, causing the glycine (G) at amino acid position 232 to be replaced by an alanine (A). 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	Benign	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	0.016
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.044
Sift	Benign	0.19	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.069	B;.
Vest4		0.43
MutPred		0.59		Gain of catalytic residue at Q233 (P = 0.0219);.;
MVP		0.63
MPC		0.097
ClinPred		0.40	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.48

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: rs1226582450; hg19: chr13-47351664;