chr21-32639778-G-A

Variant summary

Our verdict is Benign. The variant received -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. 17/21 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1197T) has been classified 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

1
16
Splicing: ADA: 0.000008912
2

Clinical Significance

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

Conservation

PhyloP100: 0.866

Publications

9 publications found
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 Gene-Disease associations (from GenCC):
  • genetic developmental and epileptic encephalopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • developmental and epileptic encephalopathy, 53
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • early-onset Parkinson disease 20
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • undetermined early-onset epileptic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • atypical juvenile parkinsonism
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • young-onset Parkinson disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Likely_benign. Clinvar id is 478345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNJ1NM_203446.3 linkc.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
SYNJ1ENST00000674351.1 linkc.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.:
2
Cov.:
32
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
GnomAD2 exomes
AF:
0.00148
AC:
371
AN:
250702
AF XY:
0.00139
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 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.:
5
Cov.:
29
AF XY:
0.00185
AC XY:
1346
AN XY:
726622
show subpopulations
African (AFR)
AF:
0.00134
AC:
45
AN:
33458
American (AMR)
AF:
0.00141
AC:
63
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.000306
AC:
8
AN:
26124
East Asian (EAS)
AF:
0.000378
AC:
15
AN:
39688
South Asian (SAS)
AF:
0.000464
AC:
40
AN:
86184
European-Finnish (FIN)
AF:
0.000805
AC:
43
AN:
53390
Middle Eastern (MID)
AF:
0.00208
AC:
12
AN:
5764
European-Non Finnish (NFE)
AF:
0.00223
AC:
2479
AN:
1110714
Other (OTH)
AF:
0.00252
AC:
152
AN:
60338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
140
280
421
561
701
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
94
188
282
376
470
<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
AF:
0.00193
AC:
294
AN:
152278
Hom.:
2
Cov.:
32
AF XY:
0.00172
AC XY:
128
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.00173
AC:
72
AN:
41552
American (AMR)
AF:
0.00183
AC:
28
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3470
East Asian (EAS)
AF:
0.000771
AC:
4
AN:
5188
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4826
European-Finnish (FIN)
AF:
0.000283
AC:
3
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00262
AC:
178
AN:
68028
Other (OTH)
AF:
0.00331
AC:
7
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
17
34
52
69
86
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00230
Hom.:
2
Bravo
AF:
0.00189
TwinsUK
AF:
0.00351
AC:
13
ALSPAC
AF:
0.00259
AC:
10
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00221
AC:
19
ExAC
AF:
0.00148
AC:
180
Asia WGS
AF:
0.00404
AC:
14
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
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) -

-
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

- -

-
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

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
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 -

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
T
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
N
LIST_S2
Benign
0.79
T;T;T;T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.0088
T;T;T;T;T
MetaSVM
Uncertain
-0.18
T
PhyloP100
0.87
PrimateAI
Benign
0.28
T
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
T
GERP RS
0.022
gMVP
0.091
Mutation Taster
=90/10
polymorphism

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

Other links and lift over

dbSNP: rs145937537; hg19: chr21-34012088; COSMIC: COSV59146806; API