Genetic Variant ESYT3:p.Gly10Trp (chr3-138434826-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031913.5(ESYT3):c.28G>T(p.Gly10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000629 in 1,557,948 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 2 hom. )

Consequence

ESYT3
NM_031913.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.254

Variant links:

Genes affected

ESYT3 (HGNC:24295): (extended synaptotagmin 3) Predicted to enable calcium ion binding activity and phospholipid binding activity. Predicted to be involved in endoplasmic reticulum-plasma membrane tethering and lipid transport. Located in endoplasmic reticulum-plasma membrane contact site. Is extrinsic component of cytoplasmic side of plasma membrane; integral component of plasma membrane; and intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ESYT3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12570035).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESYT3	NM_031913.5 link	c.28G>T	p.Gly10Trp	missense_variant	Exon 1 of 23	ENST00000389567.9	NP_114119.2	A0FGR9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ESYT3	ENST00000389567.9 link	c.28G>T	p.Gly10Trp	missense_variant	Exon 1 of 23	1	NM_031913.5	ENSP00000374218.4	A0FGR9-1
ESYT3	ENST00000289135.4 link	c.28G>T	p.Gly10Trp	missense_variant	Exon 1 of 8	5		ENSP00000289135.4	H7BXJ6
ESYT3	ENST00000486831.5 link	n.241G>T		non_coding_transcript_exon_variant	Exon 1 of 22	5
ESYT3	ENST00000490835.5 link	n.28G>T		non_coding_transcript_exon_variant	Exon 1 of 18	2		ENSP00000417388.1	A0FGR9-2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

164502

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

88188

show subpopulations

Gnomad AFR exome

AF:

0.000468

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000477

AC:

AN:

1405840

Hom.:

Cov.:

AF XY:

0.0000533

AC XY:

AN XY:

694412

show subpopulations

Gnomad4 AFR exome

AF:

0.00138

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000344

GnomAD4 genome

AF:

0.000204

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000362

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28G>T (p.G10W) alteration is located in exon 1 (coding exon 1) of the ESYT3 gene. This alteration results from a G to T substitution at nucleotide position 28, causing the glycine (G) at amino acid position 10 to be replaced by a tryptophan (W). 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

0.18

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.53

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.076

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.98

D;.

Vest4

0.34

MVP

0.30

MPC

0.51

ClinPred

0.45

GERP RS

0.11

Varity_R

0.10

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over