Genetic Variant ESYT3:p.Ala121Thr (chr3-138452081-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031913.5(ESYT3):c.361G>A(p.Ala121Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,607,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ESYT3
NM_031913.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.00

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 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=0.3518492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESYT3	NM_031913.5 link	c.361G>A	p.Ala121Thr	missense_variant	Exon 2 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.361G>A	p.Ala121Thr	missense_variant	Exon 2 of 23	1	NM_031913.5	ENSP00000374218.4	A0FGR9-1
ESYT3	ENST00000289135.4 link	c.361G>A	p.Ala121Thr	missense_variant	Exon 2 of 8	5		ENSP00000289135.4	H7BXJ6
ESYT3	ENST00000486831.5 link	n.574G>A		non_coding_transcript_exon_variant	Exon 2 of 22	5
ESYT3	ENST00000490835.5 link	n.361G>A		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000417388.1	A0FGR9-2

Frequencies

GnomAD3 genomes

AF:

0.0000673

AC:

AN:

148618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249168

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135032

show subpopulations

Gnomad AFR exome

AF:

0.000126

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:

0.00000617

AC:

AN:

1459074

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726056

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000673

AC:

AN:

148618

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

72630

show subpopulations

Gnomad4 AFR

AF:

0.000157

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000446

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361G>A (p.A121T) alteration is located in exon 2 (coding exon 2) of the ESYT3 gene. This alteration results from a G to A substitution at nucleotide position 361, causing the alanine (A) at amino acid position 121 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

Benign

0.14

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0056

T;.

Eigen

Benign

-0.069

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.9

M;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.43

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.035

D;D

Sift4G

Uncertain

0.030

D;T

Polyphen

0.36

B;.

Vest4

0.55

MVP

0.71

MPC

0.21

ClinPred

0.46

GERP RS

4.1

Varity_R

0.14

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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