chr21-32645717-C-T

Variant names:

• chr21-32645717-C-T
• rs917502531
• NM_203446.3:c.3320G>A

Variant summary

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

The NM_203446.3(SYNJ1):​c.3320G>A​(p.Arg1107Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,469,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64
• 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.3320G>A	p.Arg1107Gln	missense	Exon 25 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.3437G>A	p.Arg1146Gln	missense	Exon 25 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.3305G>A	p.Arg1102Gln	missense	Exon 24 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.3320G>A	p.Arg1107Gln	missense	Exon 25 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.3305G>A	p.Arg1102Gln	missense	Exon 24 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674308.1		c.3320G>A	p.Arg1107Gln	missense	Exon 25 of 32	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000126 AC: 1 AN: 79554 AF XY: 0.0000249

Gnomad AFR exome AF: 0.00

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: 0.0000319

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 19 AN: 1317906 Hom.: 0 Cov.: 31 AF XY: 0.00000933 AC XY: 6 AN XY: 642880

African (AFR) AF: 0.00 AC: 0 AN: 28616

American (AMR) AF: 0.00 AC: 0 AN: 20798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19660

East Asian (EAS) AF: 0.00 AC: 0 AN: 35368

South Asian (SAS) AF: 0.00 AC: 0 AN: 64698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4970

European-Non Finnish (NFE) AF: 0.0000182 AC: 19 AN: 1044234

Other (OTH) AF: 0.00 AC: 0 AN: 54408

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

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	0.67
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.45
Sift	Benign	0.18	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.53
MutPred		0.28		Loss of loop (P = 0.1258)
MVP		0.84
MPC		0.61
ClinPred		0.92	D
GERP RS		5.6
PromoterAI		0.039	Neutral
gMVP		0.14
Mutation Taster		=77/23	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: rs917502531; hg19: chr21-34018027;