Genetic Variant ESYT3:p.Pro23Ser (chr3-138434865-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031913.5(ESYT3):c.67C>T(p.Pro23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,397,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. P23T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ESYT3
NM_031913.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.140

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05677882).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031913.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESYT3	NM_031913.5	MANE Select	c.67C>T	p.Pro23Ser	missense	Exon 1 of 23	NP_114119.2	A0FGR9-1
ESYT3	NM_001322831.2		c.67C>T	p.Pro23Ser	missense	Exon 1 of 24	NP_001309760.1	A0FGR9-1
ESYT3	NM_001322834.2		c.67C>T	p.Pro23Ser	missense	Exon 1 of 23	NP_001309763.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESYT3	ENST00000389567.9	TSL:1 MANE Select	c.67C>T	p.Pro23Ser	missense	Exon 1 of 23	ENSP00000374218.4	A0FGR9-1
ESYT3	ENST00000942989.1		c.67C>T	p.Pro23Ser	missense	Exon 1 of 23	ENSP00000613048.1
ESYT3	ENST00000942987.1		c.67C>T	p.Pro23Ser	missense	Exon 1 of 23	ENSP00000613046.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1397430

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

689198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31532

American (AMR)

AF:

0.00

AC:

AN:

35744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

35774

South Asian (SAS)

AF:

0.00

AC:

AN:

79164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4306

European-Non Finnish (NFE)

AF:

0.0000204

AC:

AN:

1078876

Other (OTH)

AF:

0.0000173

AC:

AN:

57830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.5

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0039

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.56

M_CAP

Benign

0.071

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-0.14

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.44

REVEL

Benign

0.016

Sift

Benign

0.55

Sift4G

Benign

0.81

Polyphen

0.020

Vest4

0.083

MutPred

0.17

Gain of phosphorylation at P23 (P = 0.0271)

MVP

0.10

MPC

0.14

ClinPred

0.028

GERP RS

2.1

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.021

gMVP

0.70

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over