21-32688315-G-C

Variant names:

• chr21-32688315-G-C
• rs1046699971
• NM_203446.3:c.842C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_203446.3(SYNJ1):​c.842C>G​(p.Ala281Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. A281V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.24
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

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.842C>G	p.Ala281Gly	missense	Exon 7 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.959C>G	p.Ala320Gly	missense	Exon 7 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.842C>G	p.Ala281Gly	missense	Exon 7 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.842C>G	p.Ala281Gly	missense	Exon 7 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.842C>G	p.Ala281Gly	missense	Exon 7 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000429236.5	TSL:1	c.842C>G	p.Ala281Gly	missense	Exon 7 of 16	ENSP00000413649.1	C9JW66

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.71		Gain of disorder (P = 0.0974)
MVP		0.84
MPC		1.5
ClinPred		0.99	D
GERP RS		6.2
gMVP		0.53
Mutation Taster		=32/68	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: rs1046699971; hg19: chr21-34060625;