rs115648918

chr21-32631801-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The ENST00000433931.7(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 ENST00000433931.7 missense, splice_region
• Scores: Splicing: ADA: 0.001183
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.216

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 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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNJ1	NM_203446.3	c.*4G>A		splice_region_variant, 3_prime_UTR_variant	33/33	ENST00000674351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNJ1	ENST00000674351.1	c.*4G>A		splice_region_variant, 3_prime_UTR_variant	33/33		NM_203446.3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152124 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000441 AC XY: 58 AN XY: 131452

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.: 0 Cov.: 33 AF XY: 0.000261 AC XY: 188 AN XY: 721430

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.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74430

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.: 0

Bravo AF: 0.00198

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

SYNJ1-related disorder Benign:1

Likely benign, criteria provided, single submitter

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2021

This variant is associated with the following publications: (PMID: 27393345) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	13
Dann	Benign	0.87
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.30	T;T
Vest4		0.038
MVP		0.65
MPC		0.095
ClinPred		0.0020	T
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

Other links and lift over

dbSNP: rs115648918; hg19: chr21-34004111;