rs946267411

Variant names:

• chr21-32645747-T-C
• rs946267411
• NM_203446.3:c.3290A>G

Variant summary

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

The NM_203446.3(SYNJ1):​c.3290A>G​(p.Lys1097Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,313,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084127486).

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.3290A>G	p.Lys1097Arg	missense	Exon 25 of 33	NP_982271.3
	SYNJ1	NM_003895.4		c.3407A>G	p.Lys1136Arg	missense	Exon 25 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.3275A>G	p.Lys1092Arg	missense	Exon 24 of 28	NP_001153778.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.3290A>G	p.Lys1097Arg	missense	Exon 25 of 33	ENSP00000501530.1
	SYNJ1	ENST00000630077.3	TSL:1	c.3275A>G	p.Lys1092Arg	missense	Exon 24 of 28	ENSP00000487560.1
	SYNJ1	ENST00000674308.1		c.3290A>G	p.Lys1097Arg	missense	Exon 25 of 32	ENSP00000501426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1313242 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 638866

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28586

American (AMR) AF: 0.00 AC: 0 AN: 22026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19634

East Asian (EAS) AF: 0.00 AC: 0 AN: 35022

South Asian (SAS) AF: 0.00 AC: 0 AN: 65058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5224

European-Non Finnish (NFE) AF: 9.63e-7 AC: 1 AN: 1038838

Other (OTH) AF: 0.00 AC: 0 AN: 54188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.080
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.084	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.89	L
PhyloP100		1.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.35		Loss of ubiquitination at K1097 (P = 0.0019)
MVP		0.70
MPC		0.098
ClinPred		0.15	T
GERP RS		4.4
PromoterAI		-0.00040	Neutral
gMVP		0.090
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs946267411; hg19: chr21-34018057;