rs61750217

Variant names:

• chr21-32631476-C-T
• rs61750217
• ENST00000630077.3:c.4100G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003895.4(SYNJ1):​c.4358G>A​(p.Gly1453Glu) variant causes a missense change. The variant allele was found at a frequency of 0.013 in 1,614,048 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (15 hom., cov: 33)
  • Exomes 𝑓: 0.013 (163 hom.)
• Consequence: SYNJ1 NM_003895.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.38
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007054746).
• BP6: Variant 21-32631476-C-T is Benign according to our data. Variant chr21-32631476-C-T is described in ClinVar as Benign. ClinVar VariationId is 478356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00983 (1497/152242) while in subpopulation SAS AF = 0.017 (82/4818). AF 95% confidence interval is 0.0141. There are 15 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

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.*329G>A		3_prime_UTR	Exon 33 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.4358G>A	p.Gly1453Glu	missense	Exon 32 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.4100G>A	p.Gly1367Glu	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.4100G>A	p.Gly1367Glu	missense	Exon 28 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674351.1	MANE Select	c.*329G>A		3_prime_UTR	Exon 33 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000674308.1		c.4241G>A	p.Gly1414Glu	missense	Exon 32 of 32	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152124 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00642

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0127 AC: 3187 AN: 251122 AF XY: 0.0143

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00571

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00634

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0133 AC: 19489 AN: 1461806 Hom.: 163 Cov.: 30 AF XY: 0.0140 AC XY: 10212 AN XY: 727190

African (AFR) AF: 0.00284 AC: 95 AN: 33480

American (AMR) AF: 0.00691 AC: 309 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 411 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0236 AC: 2032 AN: 86248

European-Finnish (FIN) AF: 0.00627 AC: 335 AN: 53402

Middle Eastern (MID) AF: 0.0477 AC: 275 AN: 5768

European-Non Finnish (NFE) AF: 0.0137 AC: 15179 AN: 1111962

Other (OTH) AF: 0.0141 AC: 852 AN: 60396

GnomAD4 genome AF: 0.00983 AC: 1497 AN: 152242 Hom.: 15 Cov.: 33 AF XY: 0.00974 AC XY: 725 AN XY: 74440

African (AFR) AF: 0.00253 AC: 105 AN: 41536

American (AMR) AF: 0.00955 AC: 146 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4818

European-Finnish (FIN) AF: 0.00642 AC: 68 AN: 10596

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 977 AN: 68034

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0133 Hom.: 57

Bravo AF: 0.00989

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0136 AC: 117

ExAC AF: 0.0137 AC: 1661

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0163

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.68	T
PhyloP100		5.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.093
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.32	T
Vest4		0.38
MPC		0.60
ClinPred		0.019	T
GERP RS		5.1
gMVP		0.31
Mutation Taster		=91/9	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: rs61750217; hg19: chr21-34003786; COSMIC: COSV99050430; COSMIC: COSV99050430;