rs114053718

Variant names:

• chr21-32656885-A-G
• rs114053718
• NM_203446.3:c.2597T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-32656885-A-G
• chr21-32656885-A-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_203446.3(SYNJ1):​c.2597T>C​(p.Ile866Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,614,186 control chromosomes in the GnomAD database, including 1 homozygotes. 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. I866V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (1 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.10
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000705 (103/1461822) while in subpopulation AFR AF = 0.00114 (38/33476). AF 95% confidence interval is 0.000849. There are 1 homozygotes in GnomAdExome4. There are 48 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2597T>C	p.Ile866Thr	missense	Exon 21 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.2714T>C	p.Ile905Thr	missense	Exon 21 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.2582T>C	p.Ile861Thr	missense	Exon 20 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.2597T>C	p.Ile866Thr	missense	Exon 21 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.2582T>C	p.Ile861Thr	missense	Exon 20 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674308.1		c.2597T>C	p.Ile866Thr	missense	Exon 21 of 32	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.000478

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251016 AF XY: 0.000118

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1461822 Hom.: 1 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727204

African (AFR) AF: 0.00114 AC: 38 AN: 33476

American (AMR) AF: 0.000604 AC: 27 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111988

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74512

African (AFR) AF: 0.000481 AC: 20 AN: 41594

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.55	P
Vest4		0.84
MVP		0.94
MPC		0.51
ClinPred		0.35	T
GERP RS		5.6
gMVP		0.91
Mutation Taster		=39/61	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: rs114053718; hg19: chr21-34029195;