chr21-32726890-C-T

Variant names:

• chr21-32726890-C-T
• rs61750221
• NM_203446.3:c.6G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

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.6G>A	p.Ala2Ala	synonymous	Exon 2 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.123G>A	p.Ala41Ala	synonymous	Exon 2 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.6G>A	p.Ala2Ala	synonymous	Exon 2 of 28	NP_001153778.1	A0A0D9SGJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNJ1	ENST00000674351.1	MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 2 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.6G>A	p.Ala2Ala	synonymous	Exon 2 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000429236.5	TSL:1	c.6G>A	p.Ala2Ala	synonymous	Exon 2 of 16	ENSP00000413649.1	C9JW66

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

GnomAD2 exomes AF: 0.00510 AC: 1283 AN: 251350 AF XY: 0.00512

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 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

African (AFR) AF: 0.00128 AC: 43 AN: 33474

American (AMR) AF: 0.00427 AC: 191 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00773 AC: 202 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00157 AC: 135 AN: 86246

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11856 AN: 1111976

Other (OTH) AF: 0.00851 AC: 514 AN: 60388

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

African (AFR) AF: 0.00205 AC: 85 AN: 41534

American (AMR) AF: 0.00582 AC: 89 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4834

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00954 AC: 649 AN: 68018

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53 (2)
-	-	1	SYNJ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		1.5
PromoterAI		-0.14	Neutral
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs61750221; hg19: chr21-34099201;