21-32694317-GAA-GA

Variant names:

• chr21-32694317-GA-G
• rs202044634
• NM_203446.3:c.706-7delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_203446.3(SYNJ1):​c.706-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 1,494,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SYNJ1 NM_203446.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65
• Publications: 2 publications found

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]

SYNJ1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 53

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, PanelApp Australia
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atypical juvenile parkinsonism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 21-32694317-GA-G is Benign according to our data. Variant chr21-32694317-GA-G is described in ClinVar as Benign. ClinVar VariationId is 793252.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203446.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	NM_203446.3	MANE Select	c.706-7delT		splice_region intron	N/A	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.823-7delT		splice_region intron	N/A	NP_003886.3
	SYNJ1	NM_001160306.2		c.706-7delT		splice_region intron	N/A	NP_001153778.1	A0A0D9SGJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.706-7delT		splice_region intron	N/A	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.706-7delT		splice_region intron	N/A	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000429236.5	TSL:1	c.706-7delT		splice_region intron	N/A	ENSP00000413649.1	C9JW66

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000977

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 20 AN: 152684 AF XY: 0.000119

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000647

GnomAD4 exome AF: 0.0000379 AC: 51 AN: 1344200 Hom.: 0 Cov.: 27 AF XY: 0.0000405 AC XY: 27 AN XY: 667072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000216 AC: 6 AN: 27722

American (AMR) AF: 0.000187 AC: 5 AN: 26688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22236

East Asian (EAS) AF: 0.0000298 AC: 1 AN: 33524

South Asian (SAS) AF: 0.0000708 AC: 5 AN: 70596

European-Finnish (FIN) AF: 0.0000399 AC: 2 AN: 50110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.0000285 AC: 30 AN: 1053440

Other (OTH) AF: 0.0000366 AC: 2 AN: 54650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150278 Hom.: 0 Cov.: 32 AF XY: 0.0000273 AC XY: 2 AN XY: 73262

African (AFR) AF: 0.0000974 AC: 4 AN: 41050

American (AMR) AF: 0.00 AC: 0 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67480

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs202044634; hg19: chr21-34066627; COSMIC: COSV59147070; COSMIC: COSV59147070;