ENST00000630077.3:c.4382C>T

Variant names:

• chr21-32631194-G-A
• rs76056543
• ENST00000630077.3:c.4382C>T
• SYNJ1 p.Pro1461Leu

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000630077.3(SYNJ1):​c.4382C>T​(p.Pro1461Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,614,146 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (7 hom.)
• Consequence: SYNJ1 ENST00000630077.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.16
• 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), PanelApp Australia, Ambry Genetics
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035976171).
• BP6: Variant 21-32631194-G-A is Benign according to our data. Variant chr21-32631194-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00558 (849/152274) while in subpopulation AFR AF = 0.0195 (810/41556). AF 95% confidence interval is 0.0184. There are 8 homozygotes in GnomAd4. There are 391 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000630077.3. 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.*611C>T		3_prime_UTR	Exon 33 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.4640C>T	p.Pro1547Leu	missense	Exon 32 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.4382C>T	p.Pro1461Leu	missense	Exon 28 of 28	NP_001153778.1	A0A0D9SGJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000630077.3	TSL:1	c.4382C>T	p.Pro1461Leu	missense	Exon 28 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674351.1	MANE Select	c.*611C>T		3_prime_UTR	Exon 33 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000674308.1		c.4523C>T	p.Pro1508Leu	missense	Exon 32 of 32	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152156 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00158 AC: 398 AN: 251462 AF XY: 0.00124

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000575 AC: 841 AN: 1461872 Hom.: 7 Cov.: 30 AF XY: 0.000465 AC XY: 338 AN XY: 727238

African (AFR) AF: 0.0216 AC: 724 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112006

Other (OTH) AF: 0.00116 AC: 70 AN: 60396

GnomAD4 genome AF: 0.00558 AC: 849 AN: 152274 Hom.: 8 Cov.: 33 AF XY: 0.00525 AC XY: 391 AN XY: 74462

African (AFR) AF: 0.0195 AC: 810 AN: 41556

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00154 Hom.: 2

Bravo AF: 0.00645

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.029
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.26	T
gMVP		0.17
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

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

Other links and lift over

dbSNP: rs76056543;

hg19: chr21-34003504;

COSMIC: COSV99050431;

COSMIC: COSV99050431;