rs145937537

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_203446.3(SYNJ1):c.3590C>T(p.Thr1197Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,612,648 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 5 hom. )

Consequence

SYNJ1
NM_203446.3 missense, splice_region

Scores

Splicing: ADA: 0.000008912

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.866

Variant links:

Genes affected

SYNJ1 (HGNC:11503): (synaptojanin 1) This gene encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate. As such, expression of this enzyme may affect synaptic transmission and membrane trafficking. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

SYNJ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008764178).

BP6

Variant 21-32639778-G-A is Benign according to our data. Variant chr21-32639778-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-32639778-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00193 (294/152278) while in subpopulation NFE AF= 0.00262 (178/68028). AF 95% confidence interval is 0.0023. There are 2 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3 link	c.3590C>T	p.Thr1197Met	missense_variant, splice_region_variant	Exon 30 of 33	ENST00000674351.1	NP_982271.3	O43426-2C9JFZ1Q05CZ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1 link	c.3590C>T	p.Thr1197Met	missense_variant, splice_region_variant	Exon 30 of 33		NM_203446.3	ENSP00000501530.1		O43426-2

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

293

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00148

AC:

371

AN:

250702

Hom.:

AF XY:

0.00139

AC XY:

189

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00196

AC:

2857

AN:

1460370

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1346

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.00223

Gnomad4 OTH exome

AF:

0.00252

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152278

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00262

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00248

Hom.:

Bravo

AF:

0.00189

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00148

AC:

180

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00235

EpiControl

AF:

0.00213

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNJ1: BS2 -

Sep 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27393345) -

Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SYNJ1-related disorder

Benign:1

Jan 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

6.1

DANN

Benign

0.97

DEOGEN2

Benign

0.31

.;T;.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Uncertain

-0.18

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.3

N;N;.;N;N

REVEL

Benign

0.24

Sift

Benign

0.071

T;T;.;T;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.0050

B;.;.;B;.

Vest4

0.14

MVP

0.47

MPC

0.14

ClinPred

0.0081

GERP RS

0.022

gMVP

0.091

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000089

dbscSNV1_RF

Benign

0.086

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