rs61756694

chr21-32695189-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_203446.3(SYNJ1):c.573A>G(p.Thr191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,614,172 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (37 hom.)
• Consequence: SYNJ1 NM_203446.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.220

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 21-32695189-T-C is Benign according to our data. Variant chr21-32695189-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-32695189-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00408 (621/152336) while in subpopulation NFE AF= 0.00631 (429/68032). AF 95% confidence interval is 0.00581. There are 3 homozygotes in gnomad4. There are 292 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNJ1	NM_203446.3	c.573A>G	p.Thr191=	synonymous_variant	5/33	ENST00000674351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNJ1	ENST00000674351.1	c.573A>G	p.Thr191=	synonymous_variant	5/33		NM_203446.3

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 623 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00632

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00485 AC: 1220 AN: 251470 Hom.: 8 AF XY: 0.00531 AC XY: 721 AN XY: 135908

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00568

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.00743

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00623 AC: 9108 AN: 1461836 Hom.: 37 Cov.: 30 AF XY: 0.00632 AC XY: 4599 AN XY: 727220

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00555

Gnomad4 FIN exome AF: 0.00358

Gnomad4 NFE exome AF: 0.00714

Gnomad4 OTH exome AF: 0.00513

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00392 AC XY: 292 AN XY: 74502

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00492 Hom.: 0

Bravo AF: 0.00412

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.00496

EpiControl AF: 0.00581

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNJ1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

SYNJ1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2019

This variant is classified as 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_noAF	Benign	-0.59
Cadd	Benign	4.8
Dann	Benign	0.38

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

LitVar

Other links and lift over

dbSNP: rs61756694; hg19: chr21-34067499;