21-32631062-G-T

Variant names:

• chr21-32631062-G-T
• rs1352834939
• ENST00000630077.3:c.4514C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003895.4(SYNJ1):​c.4772C>A​(p.Pro1591His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYNJ1 NM_003895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101968735).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003895.4. 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.*743C>A		3_prime_UTR	Exon 33 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.4772C>A	p.Pro1591His	missense	Exon 32 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.4514C>A	p.Pro1505His	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.4514C>A	p.Pro1505His	missense	Exon 28 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674351.1	MANE Select	c.*743C>A		3_prime_UTR	Exon 33 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000674308.1		c.4655C>A	p.Pro1552His	missense	Exon 32 of 32	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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	Benign	0.086
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.059
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.17	T
Vest4		0.15
MVP		0.26
MPC		0.41
ClinPred		0.26	T
GERP RS		3.0
gMVP		0.26
Mutation Taster		=97/3	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: rs1352834939; hg19: chr21-34003372;