rs61750220

chr21-32638903-C-Achr21-32638903-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_203446.3(SYNJ1):c.3915+5G>T variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00232 in 1,588,414 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (41 hom.)
• Consequence: SYNJ1 NM_203446.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.34

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 21-32638903-C-A is Benign according to our data. Variant chr21-32638903-C-A is described in ClinVar as [Benign]. Clinvar id is 478342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1913/152196) while in subpopulation AFR AF= 0.0435 (1803/41494). AF 95% confidence interval is 0.0418. There are 47 homozygotes in gnomad4. There are 875 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNJ1	NM_203446.3	c.3915+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000674351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNJ1	ENST00000674351.1	c.3915+5G>T		splice_donor_5th_base_variant, intron_variant			NM_203446.3

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1911 AN: 152078 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00318 AC: 769 AN: 241836 Hom.: 15 AF XY: 0.00223 AC XY: 292 AN XY: 131130

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000814

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00124 AC: 1780 AN: 1436218 Hom.: 41 Cov.: 30 AF XY: 0.00106 AC XY: 757 AN XY: 711406

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000594

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.0126 AC: 1913 AN: 152196 Hom.: 47 Cov.: 32 AF XY: 0.0118 AC XY: 875 AN XY: 74414

Gnomad4 AFR AF: 0.0435

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00288 Hom.: 13

Bravo AF: 0.0138

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61750220; hg19: chr21-34011213;