NM_203446.3:c.1609G>A

Variant names:

• chr21-32673457-C-T
• rs1555898799
• NM_203446.3:c.1609G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_203446.3(SYNJ1):​c.1609G>A​(p.Val537Ile) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31950665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.1609G>A	p.Val537Ile	missense_variant	Exon 14 of 33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.1609G>A	p.Val537Ile	missense_variant	Exon 14 of 33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 Uncertain:1

Sep 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with SYNJ1-related disease. This sequence change replaces valine with isoleucine at codon 576 of the SYNJ1 protein (p.Val576Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;.;T;T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.1	L;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.60	N;N;.;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.097	T;T;.;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;.
Polyphen		0.0020	B;.;.;B;.;.
Vest4		0.19
MutPred		0.46		Gain of catalytic residue at V537 (P = 0.1752);.;.;.;.;.;
MVP		0.78
MPC		0.48
ClinPred		0.72	D
GERP RS		4.3
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555898799; hg19: chr21-34045767;