Genetic Variant SYNJ1:p.Pro1266Leu (chr21-32639026-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_203446.3(SYNJ1):c.3797C>T(p.Pro1266Leu) variant causes a missense change. 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. P1266S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SYNJ1
NM_203446.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

Publications

1 publications found

Variant links:

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

SYNJ1 links:

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ACMG classification

Classification was made for transcript

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, 0.772

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNJ1	NM_203446.3	MANE Select	c.3797C>T	p.Pro1266Leu	missense	Exon 31 of 33	NP_982271.3
SYNJ1	NM_003895.4		c.3914C>T	p.Pro1305Leu	missense	Exon 31 of 32	NP_003886.3
SYNJ1	NM_001160306.2		c.3656C>T	p.Pro1219Leu	missense	Exon 27 of 28	NP_001153778.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNJ1	ENST00000674351.1	MANE Select	c.3797C>T	p.Pro1266Leu	missense	Exon 31 of 33	ENSP00000501530.1
SYNJ1	ENST00000433931.7	TSL:1	c.3914C>T	p.Pro1305Leu	missense	Exon 31 of 32	ENSP00000409667.2
SYNJ1	ENST00000630077.3	TSL:1	c.3656C>T	p.Pro1219Leu	missense	Exon 27 of 28	ENSP00000487560.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.079

MetaRNN

Pathogenic

0.77

MetaSVM

Pathogenic

0.97

PhyloP100

5.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0030

Sift4G

Benign

0.18

Polyphen

0.50

Vest4

0.65

MVP

0.81

MPC

0.54

ClinPred

0.99

GERP RS

5.4

gMVP

0.29

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over