21-32726890-C-T

Position:

• chr21-32726890-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_203446.3(SYNJ1):​c.6G>A​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,614,054 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (84 hom.)
• Consequence: SYNJ1 NM_203446.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.53

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 21-32726890-C-T is Benign according to our data. Variant chr21-32726890-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.006 (913/152248) while in subpopulation NFE AF= 0.00954 (649/68018). AF 95% confidence interval is 0.00893. There are 8 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.6G>A	p.Ala2Ala	synonymous_variant	2/33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.6G>A	p.Ala2Ala	synonymous_variant	2/33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152130 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00954

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00510 AC: 1283 AN: 251350 Hom.: 6 AF XY: 0.00512 AC XY: 695 AN XY: 135852

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00889 AC: 12999 AN: 1461806 Hom.: 84 Cov.: 30 AF XY: 0.00867 AC XY: 6305 AN XY: 727194

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00773

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00851

GnomAD4 genome AF: 0.00600 AC: 913 AN: 152248 Hom.: 8 Cov.: 32 AF XY: 0.00566 AC XY: 421 AN XY: 74440

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00954

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00656 Hom.: 2

Bravo AF: 0.00630

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SYNJ1: BP4, BP7, BS1, BS2 -

Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

SYNJ1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2020

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	-0.27
CADD	Benign	15
DANN	Benign	0.88

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: rs61750221; hg19: chr21-34099201;