rs147929290

Variant names:

• chr21-32665968-A-G
• rs147929290
• NM_203446.3:c.2120T>C
• SYNJ1 p.Ile707Thr

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_203446.3(SYNJ1):​c.2120T>C​(p.Ile707Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,610,828 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: SYNJ1 NM_203446.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.32
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• early-onset Parkinson disease 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -9 ACMG points.

• BP6: Variant 21-32665968-A-G is Benign according to our data. Variant chr21-32665968-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 544560.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000755 (115/152336) while in subpopulation NFE AF = 0.00148 (101/68026). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.2120T>C	p.Ile707Thr	missense	Exon 17 of 33	NP_982271.3	O43426-2
	SYNJ1	NM_003895.4		c.2237T>C	p.Ile746Thr	missense	Exon 17 of 32	NP_003886.3
	SYNJ1	NM_001160306.2		c.2105T>C	p.Ile702Thr	missense	Exon 16 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.2120T>C	p.Ile707Thr	missense	Exon 17 of 33	ENSP00000501530.1	O43426-2
	SYNJ1	ENST00000630077.3	TSL:1	c.2105T>C	p.Ile702Thr	missense	Exon 16 of 28	ENSP00000487560.1	A0A0D9SGJ6
	SYNJ1	ENST00000674308.1		c.2120T>C	p.Ile707Thr	missense	Exon 17 of 32	ENSP00000501426.1	O43426-1

Frequencies

GnomAD3 genomes AF: 0.000755 AC: 115 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000894 AC: 222 AN: 248188 AF XY: 0.000962

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00142 AC: 2065 AN: 1458492 Hom.: 3 Cov.: 30 AF XY: 0.00142 AC XY: 1032 AN XY: 725360

African (AFR) AF: 0.000330 AC: 11 AN: 33302

American (AMR) AF: 0.0000227 AC: 1 AN: 44060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85530

European-Finnish (FIN) AF: 0.000544 AC: 29 AN: 53336

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.00174 AC: 1929 AN: 1110628

Other (OTH) AF: 0.00156 AC: 94 AN: 60254

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74504

African (AFR) AF: 0.000265 AC: 11 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00148 AC: 101 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00128 Hom.: 7

Bravo AF: 0.000759

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.90
Sift	Benign	0.099	T
Sift4G	Benign	0.076	T
gMVP		0.93
Mutation Taster		=42/58	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs147929290;

hg19: chr21-34038278;

COSMIC: COSV105227913;

COSMIC: COSV105227913;