rs144048853

Variant names:

• chr21-32639730-C-A
• rs144048853
• NM_203446.3:c.3638G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-32639730-C-A
• chr21-32639730-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_203446.3(SYNJ1):​c.3638G>T​(p.Arg1213Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R1213W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53
• Publications: 5 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.3638G>T	p.Arg1213Leu	missense_variant	Exon 30 of 33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.3638G>T	p.Arg1213Leu	missense_variant	Exon 30 of 33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
PhyloP100		3.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N;N;.;N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0060	D;D;.;D;D
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		1.0	D;.;.;P;.
Vest4		0.62
MVP		0.77
MPC		0.58
ClinPred		0.96	D
GERP RS		5.3
gMVP		0.087
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: rs144048853; hg19: chr21-34012040;