rs115648918

Positions:

chr21-32631801-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_003895.4(SYNJ1):c.4033G>A(p.Val1345Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000406 in 1,604,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

SYNJ1
NM_003895.4 missense, splice_region

Scores

Splicing: ADA: 0.001183

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.216

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004608333).

BP6

Variant 21-32631801-C-T is Benign according to our data. Variant chr21-32631801-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-32631801-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00148 (225/152242) while in subpopulation AFR AF= 0.00481 (200/41540). AF 95% confidence interval is 0.00427. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ1	NM_203446.3 linkuse as main transcript	c.*4G>A		splice_region_variant	33/33	ENST00000674351.1	NP_982271.3	O43426-2C9JFZ1Q05CZ1
SYNJ1	NM_203446.3 linkuse as main transcript	c.*4G>A		3_prime_UTR_variant	33/33	ENST00000674351.1	NP_982271.3	O43426-2C9JFZ1Q05CZ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1 linkuse as main transcript	c.*4G>A		splice_region_variant	33/33		NM_203446.3	ENSP00000501530.1		O43426-2
SYNJ1	ENST00000674351 linkuse as main transcript	c.*4G>A		3_prime_UTR_variant	33/33		NM_203446.3	ENSP00000501530.1		O43426-2

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

224

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00480

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000618

AC:

150

AN:

242826

Hom.:

AF XY:

0.000441

AC XY:

AN XY:

131452

show subpopulations

Gnomad AFR exome

AF:

0.00485

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000155

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.000294

AC:

427

AN:

1452220

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

188

AN XY:

721430

show subpopulations

Gnomad4 AFR exome

AF:

0.00482

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.0000781

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.000767

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152242

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00481

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000411

Hom.:

Bravo

AF:

0.00198

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000807

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	This variant is associated with the following publications: (PMID: 27393345) -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

SYNJ1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.22

.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.57

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.18

.;N

REVEL

Benign

0.15

Sift

Benign

0.37

.;T

Sift4G

Benign

0.30

T;T

Vest4

0.038

MVP

0.65

MPC

0.095

ClinPred

0.0020

GERP RS

2.4

gMVP

0.035

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.22

SpliceAI score (max)

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over