rs2833929

Variant names:

• chr21-32641973-C-A
• rs2833929
• NM_203446.3:c.3518-7G>T

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.3518-7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,026 control chromosomes in the GnomAD database, including 65,816 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6113 hom., cov: 31)
  • Exomes 𝑓: 0.28 (59703 hom.)
• Consequence: SYNJ1 NM_203446.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008293
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.623
• Publications: 14 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.65).
• BP6: Variant 21-32641973-C-A is Benign according to our data. Variant chr21-32641973-C-A is described in ClinVar as Benign. ClinVar VariationId is 586760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	NM_203446.3	MANE Select	c.3518-7G>T		splice_region intron	N/A	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.3635-7G>T		splice_region intron	N/A	NP_003886.3
	SYNJ1	NM_001160306.2		c.3377-7G>T		splice_region intron	N/A	NP_001153778.1	A0A0D9SGJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.3518-7G>T		splice_region intron	N/A	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.3377-7G>T		splice_region intron	N/A	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674308.1		c.3518-7G>T		splice_region intron	N/A	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42907 AN: 151788 Hom.: 6106 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.375

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.289 AC: 72536 AN: 250784 AF XY: 0.294

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.268

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.284 AC: 414806 AN: 1461118 Hom.: 59703 Cov.: 35 AF XY: 0.286 AC XY: 207711 AN XY: 726904

African (AFR) AF: 0.269 AC: 8997 AN: 33428

American (AMR) AF: 0.274 AC: 12262 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10573 AN: 26126

East Asian (EAS) AF: 0.354 AC: 14058 AN: 39674

South Asian (SAS) AF: 0.321 AC: 27642 AN: 86210

European-Finnish (FIN) AF: 0.233 AC: 12431 AN: 53386

Middle Eastern (MID) AF: 0.345 AC: 1989 AN: 5764

European-Non Finnish (NFE) AF: 0.278 AC: 308886 AN: 1111486

Other (OTH) AF: 0.298 AC: 17968 AN: 60364

GnomAD4 genome AF: 0.283 AC: 42932 AN: 151908 Hom.: 6113 Cov.: 31 AF XY: 0.283 AC XY: 20980 AN XY: 74242

African (AFR) AF: 0.272 AC: 11254 AN: 41408

American (AMR) AF: 0.278 AC: 4244 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1382 AN: 3468

East Asian (EAS) AF: 0.345 AC: 1779 AN: 5150

South Asian (SAS) AF: 0.313 AC: 1511 AN: 4820

European-Finnish (FIN) AF: 0.227 AC: 2394 AN: 10530

Middle Eastern (MID) AF: 0.359 AC: 104 AN: 290

European-Non Finnish (NFE) AF: 0.285 AC: 19395 AN: 67958

Other (OTH) AF: 0.306 AC: 646 AN: 2110

Alfa AF: 0.290 Hom.: 3619

Bravo AF: 0.287

Asia WGS AF: 0.299 AC: 1041 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.300

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy, 53 (1)
-	-	1	Early-onset Parkinson disease 20 (1)
-	-	1	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.6
DANN	Benign	0.68
PhyloP100		-0.62
PromoterAI		0.0034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2833929; hg19: chr21-34014283; COSMIC: COSV59151924; COSMIC: COSV59151924;