21-32645668-T-C

Position:

• chr21-32645668-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.3369A>G​(p.Pro1123Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,525,346 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: SYNJ1 NM_203446.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.223

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=-0.6).
• BP6: Variant 21-32645668-T-C is Benign according to our data. Variant chr21-32645668-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-32645668-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.223 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00178 (271/151950) while in subpopulation NFE AF= 0.00328 (223/67926). AF 95% confidence interval is 0.00293. There are 0 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.3369A>G	p.Pro1123Pro	synonymous_variant	25/33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.3369A>G	p.Pro1123Pro	synonymous_variant	25/33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 151834 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00154 AC: 209 AN: 135914 Hom.: 0 AF XY: 0.00154 AC XY: 112 AN XY: 72838

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000630

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00301 AC: 4131 AN: 1373396 Hom.: 9 Cov.: 30 AF XY: 0.00288 AC XY: 1951 AN XY: 677280

Gnomad4 AFR exome AF: 0.000332

Gnomad4 AMR exome AF: 0.00138

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000138

Gnomad4 FIN exome AF: 0.000267

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00178 AC: 271 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.00174 AC XY: 129 AN XY: 74292

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00205

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SYNJ1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 14, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

SYNJ1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2019

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_noAF	Benign	-0.60
CADD	Benign	5.0
DANN	Benign	0.56

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: rs368850131; hg19: chr21-34017978;