13-46771471-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001984.2(ESD):c.794T>C(p.Ile265Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,576 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: 0.0000014 (0 hom.)
• Consequence: ESD NM_001984.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.05

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESD	NM_001984.2	c.794T>C	p.Ile265Thr	missense_variant	10/10	ENST00000378720.8
ESD	XM_005266278.4	c.794T>C	p.Ile265Thr	missense_variant	10/10
ESD	XM_011534954.2	c.794T>C	p.Ile265Thr	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESD	ENST00000378720.8	c.794T>C	p.Ile265Thr	missense_variant	10/10	1	NM_001984.2	P1
ESD	ENST00000378697.5	c.707T>C	p.Ile236Thr	missense_variant	11/11	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249944 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454576 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000247 AC: 3

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

Apr 05, 2023

The c.794T>C (p.I265T) alteration is located in exon 10 (coding exon 8) of the ESD gene. This alteration results from a T to C substitution at nucleotide position 794, causing the isoleucine (I) at amino acid position 265 to be replaced by a threonine (T). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.80
MutPred		0.62		Gain of catalytic residue at A266 (P = 0.0012);.;
MVP		0.80
MPC		0.50
ClinPred		0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.54

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: rs747238256; hg19: chr13-47345606;