rs76502784

Variant names:

• chr21-32699829-T-C
• rs76502784
• NM_203446.3:c.479+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203446.3(SYNJ1):​c.479+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,603,016 control chromosomes in the GnomAD database, including 1,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (110 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1712 hom.)
• Consequence: SYNJ1 NM_203446.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.30
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-32699829-T-C is Benign according to our data. Variant chr21-32699829-T-C is described in ClinVar as Benign. ClinVar VariationId is 478364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.069 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.479+9A>G		intron_variant	Intron 4 of 32	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.479+9A>G		intron_variant	Intron 4 of 32		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5111 AN: 152008 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.0750

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0377 AC: 9181 AN: 243770 AF XY: 0.0379

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0746

Gnomad FIN exome AF: 0.0380

Gnomad NFE exome AF: 0.0440

Gnomad OTH exome AF: 0.0356

GnomAD4 exome AF: 0.0461 AC: 66837 AN: 1450890 Hom.: 1712 Cov.: 31 AF XY: 0.0455 AC XY: 32825 AN XY: 720824

African (AFR) AF: 0.0142 AC: 465 AN: 32746

American (AMR) AF: 0.0134 AC: 572 AN: 42826

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 494 AN: 25666

East Asian (EAS) AF: 0.0706 AC: 2790 AN: 39522

South Asian (SAS) AF: 0.0363 AC: 3084 AN: 84852

European-Finnish (FIN) AF: 0.0373 AC: 1984 AN: 53154

Middle Eastern (MID) AF: 0.0132 AC: 75 AN: 5690

European-Non Finnish (NFE) AF: 0.0497 AC: 54991 AN: 1106604

Other (OTH) AF: 0.0398 AC: 2382 AN: 59830

GnomAD4 genome AF: 0.0336 AC: 5107 AN: 152126 Hom.: 110 Cov.: 32 AF XY: 0.0328 AC XY: 2439 AN XY: 74360

African (AFR) AF: 0.0155 AC: 642 AN: 41506

American (AMR) AF: 0.0211 AC: 322 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.0751 AC: 389 AN: 5178

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4816

European-Finnish (FIN) AF: 0.0314 AC: 332 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0462 AC: 3138 AN: 67976

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0386 Hom.: 63

Bravo AF: 0.0316

Asia WGS AF: 0.0480 AC: 169 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0408

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 09, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76502784; hg19: chr21-34072139;