chr21-32645668-T-C

Variant names:

• chr21-32645668-T-C
• rs368850131
• NM_203446.3:c.3369A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_203446.3(SYNJ1):​c.3369A>G​(p.Pro1123Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,525,346 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1123P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: SYNJ1 NM_203446.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.223
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.014).
• BP6: Variant 21-32645668-T-C is Benign according to our data. Variant chr21-32645668-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.223 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/151950) while in subpopulation NFE AF = 0.00328 (223/67926). AF 95% confidence interval is 0.00293. There are 0 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	NM_203446.3	MANE Select	c.3369A>G	p.Pro1123Pro	synonymous	Exon 25 of 33	NP_982271.3
	SYNJ1	NM_003895.4		c.3486A>G	p.Pro1162Pro	synonymous	Exon 25 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.3354A>G	p.Pro1118Pro	synonymous	Exon 24 of 28	NP_001153778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.3369A>G	p.Pro1123Pro	synonymous	Exon 25 of 33	ENSP00000501530.1
	SYNJ1	ENST00000433931.7	TSL:1	c.3486A>G	p.Pro1162Pro	synonymous	Exon 25 of 32	ENSP00000409667.2
	SYNJ1	ENST00000630077.3	TSL:1	c.3354A>G	p.Pro1118Pro	synonymous	Exon 24 of 28	ENSP00000487560.1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 151834 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00154 AC: 209 AN: 135914 AF XY: 0.00154

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00301 AC: 4131 AN: 1373396 Hom.: 9 Cov.: 30 AF XY: 0.00288 AC XY: 1951 AN XY: 677280

African (AFR) AF: 0.000332 AC: 10 AN: 30124

American (AMR) AF: 0.00138 AC: 37 AN: 26852

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 36 AN: 22310

East Asian (EAS) AF: 0.00 AC: 0 AN: 37300

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72686

European-Finnish (FIN) AF: 0.000267 AC: 13 AN: 48624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4536

European-Non Finnish (NFE) AF: 0.00367 AC: 3940 AN: 1074392

Other (OTH) AF: 0.00166 AC: 94 AN: 56572

GnomAD4 genome AF: 0.00178 AC: 271 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.00174 AC XY: 129 AN XY: 74292

African (AFR) AF: 0.000507 AC: 21 AN: 41436

American (AMR) AF: 0.00111 AC: 17 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 67926

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00205

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 09, 2021

GeneDx

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

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNJ1: BP4, BP7

not specified Benign:1

Sep 14, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNJ1-related disorder Benign:1

Apr 05, 2019

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.0
DANN	Benign	0.56
PhyloP100		-0.22
PromoterAI		0.025	Neutral
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs368850131; hg19: chr21-34017978;