rs61756694

Variant names:

• chr21-32695189-T-C
• rs61756694
• NM_203446.3:c.573A>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.573A>G​(p.Thr191Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,614,172 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (37 hom.)
• Consequence: SYNJ1 NM_203446.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.220
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 21-32695189-T-C is Benign according to our data. Variant chr21-32695189-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00408 (621/152336) while in subpopulation NFE AF = 0.00631 (429/68032). AF 95% confidence interval is 0.00581. There are 3 homozygotes in GnomAd4. There are 292 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	NM_203446.3	MANE Select	c.573A>G	p.Thr191Thr	synonymous	Exon 5 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.690A>G	p.Thr230Thr	synonymous	Exon 5 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.573A>G	p.Thr191Thr	synonymous	Exon 5 of 28	NP_001153778.1	A0A0D9SGJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.573A>G	p.Thr191Thr	synonymous	Exon 5 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.573A>G	p.Thr191Thr	synonymous	Exon 5 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000429236.5	TSL:1	c.573A>G	p.Thr191Thr	synonymous	Exon 5 of 16	ENSP00000413649.1	C9JW66

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 623 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00632

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00485 AC: 1220 AN: 251470 AF XY: 0.00531

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.00743

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00623 AC: 9108 AN: 1461836 Hom.: 37 Cov.: 30 AF XY: 0.00632 AC XY: 4599 AN XY: 727220

African (AFR) AF: 0.00134 AC: 45 AN: 33478

American (AMR) AF: 0.00195 AC: 87 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00555 AC: 479 AN: 86258

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.00714 AC: 7938 AN: 1111984

Other (OTH) AF: 0.00513 AC: 310 AN: 60394

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00392 AC XY: 292 AN XY: 74502

African (AFR) AF: 0.00115 AC: 48 AN: 41574

American (AMR) AF: 0.00464 AC: 71 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00631 AC: 429 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00492 Hom.: 0

Bravo AF: 0.00412

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.00496

EpiControl AF: 0.00581

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)
-	-	1	SYNJ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.8
DANN	Benign	0.38
PhyloP100		-0.22
Mutation Taster		=99/1	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: rs61756694; hg19: chr21-34067499;