rs946267411

chr21-32645747-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203446.3(SYNJ1):c.3290A>G(p.Lys1097Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,313,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084127486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNJ1	NM_203446.3	c.3290A>G	p.Lys1097Arg	missense_variant	25/33	ENST00000674351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNJ1	ENST00000674351.1	c.3290A>G	p.Lys1097Arg	missense_variant	25/33		NM_203446.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1313242 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 638866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SYNJ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 478340). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1136 of the SYNJ1 protein (p.Lys1136Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.084	T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.89	L;.;.;.;.
MutationTaster	Benign	0.77	N;N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.29	N;N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.22	T;T;.;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.0020	B;.;.;B;.
Vest4		0.11
MutPred		0.35		Loss of ubiquitination at K1097 (P = 0.0019);.;.;.;.;
MVP		0.70
MPC		0.098
ClinPred		0.15	T
GERP RS		4.4
gMVP		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs946267411; hg19: chr21-34018057;