rs1238065971

Variant names:

• chr21-32678689-A-G
• rs1238065971
• NM_203446.3:c.1466T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_203446.3(SYNJ1):​c.1466T>C​(p.Leu489Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L489V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52
• Publications: 0 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, PanelApp Australia
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, 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: Uncertain_significance. The variant received 0 ACMG points.

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.1466T>C	p.Leu489Ser	missense	Exon 12 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.1583T>C	p.Leu528Ser	missense	Exon 12 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.1475T>C	p.Leu492Ser	missense	Exon 12 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.1466T>C	p.Leu489Ser	missense	Exon 12 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.1475T>C	p.Leu492Ser	missense	Exon 12 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000429236.5	TSL:1	c.1475T>C	p.Leu492Ser	missense	Exon 12 of 16	ENSP00000413649.1	C9JW66

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246650 AF XY: 0.00

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459548 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726052

African (AFR) AF: 0.0000900 AC: 3 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111346

Other (OTH) AF: 0.0000166 AC: 1 AN: 60296

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.26
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.51		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.47
MPC		1.8
ClinPred		0.95	D
GERP RS		6.0
gMVP		0.87
Mutation Taster		=26/74	disease causing

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: rs1238065971; hg19: chr21-34050999;