dbSNP rs145937537: SYNJ1:p.Thr1197Met (chr21-32639778-G-A) – ACMG Classification: Benign (-20 pts)

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. 18/22 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

Splicing: ADA: 0.000008912

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.866

Publications

10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
early-onset Parkinson disease 20
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
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

SYNJ1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_203446.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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 ClinVar as Likely_benign. ClinVar VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203446.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNJ1	NM_203446.3	MANE Select	c.3590C>T	p.Thr1197Met	missense splice_region	Exon 30 of 33	NP_982271.3	O43426-2
SYNJ1	NM_003895.4		c.3707C>T	p.Thr1236Met	missense splice_region	Exon 30 of 32	NP_003886.3
SYNJ1	NM_001160306.2		c.3449C>T	p.Thr1150Met	missense splice_region	Exon 26 of 28	NP_001153778.1	A0A0D9SGJ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNJ1	ENST00000674351.1	MANE Select	c.3590C>T	p.Thr1197Met	missense splice_region	Exon 30 of 33	ENSP00000501530.1	O43426-2
SYNJ1	ENST00000630077.3	TSL:1	c.3449C>T	p.Thr1150Met	missense splice_region	Exon 26 of 28	ENSP00000487560.1	A0A0D9SGJ6
SYNJ1	ENST00000674308.1		c.3590C>T	p.Thr1197Met	missense splice_region	Exon 30 of 32	ENSP00000501426.1	O43426-1

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

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.:

Cov.:

AF XY:

0.00185

AC XY:

1346

AN XY:

726622

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33458

American (AMR)

AF:

0.00141

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26124

East Asian (EAS)

AF:

0.000378

AC:

AN:

39688

South Asian (SAS)

AF:

0.000464

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.000805

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00208

AC:

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

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

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.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41552

American (AMR)

AF:

0.00183

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00262

AC:

178

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.00189

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00235

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)

SYNJ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

6.1

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.79

M_CAP

Benign

0.024

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

-0.18

PhyloP100

0.87

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.3

REVEL

Benign

0.24

Sift

Benign

0.071

Sift4G

Benign

0.24

gMVP

0.091

Mutation Taster

=90/10

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over