chr21-32688315-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
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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

Selected	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
	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

Ensembl Transcripts

Selected	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
	SYNJ1	ENST00000433931.7	TSL:1	c.959C>G	p.Ala320Gly	missense	Exon 7 of 32	ENSP00000409667.2
	SYNJ1	ENST00000630077.3	TSL:1	c.842C>G	p.Ala281Gly	missense	Exon 7 of 28	ENSP00000487560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 Uncertain:1

Jul 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with glycine at codon 320 of the SYNJ1 protein (p.Ala320Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SYNJ1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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;