rs373820739

Variant names:

• chr21-32666479-C-G
• rs373820739
• NM_203446.3:c.1906G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-32666479-C-G
• chr21-32666479-C-T

Variant summary

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

The NM_203446.3(SYNJ1):​c.1906G>C​(p.Val636Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V636I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.1906G>C	p.Val636Leu	missense_variant	Exon 16 of 33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.1906G>C	p.Val636Leu	missense_variant	Exon 16 of 33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;.;D;D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Uncertain	-0.0014	T
MutationAssessor	Benign	0.85	L;.;.;.;.;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.8	D;D;.;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D;.;D;T;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.
Polyphen		0.82	P;.;.;P;.;.
Vest4		0.71
MutPred		0.46		Gain of sheet (P = 0.1945);.;.;.;.;.;
MVP		0.75
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
gMVP		0.63
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs373820739; hg19: chr21-34038789;