rs61750217

Positions:

• chr21-32631476-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000433931.7(SYNJ1):​c.4358G>A​(p.Gly1453Glu) variant causes a missense change. The variant allele was found at a frequency of 0.013 in 1,614,048 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (15 hom., cov: 33)
  • Exomes 𝑓: 0.013 (163 hom.)
• Consequence: SYNJ1 ENST00000433931.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.38

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007054746).
• BP6: Variant 21-32631476-C-T is Benign according to our data. Variant chr21-32631476-C-T is described in ClinVar as [Benign]. Clinvar id is 478356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-32631476-C-T is described in Lovd as [Likely_benign]. Variant chr21-32631476-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00983 (1497/152242) while in subpopulation SAS AF= 0.017 (82/4818). AF 95% confidence interval is 0.0141. There are 15 homozygotes in gnomad4. There are 725 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.*329G>A		3_prime_UTR_variant	33/33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.*329G>A		3_prime_UTR_variant	33/33		NM_203446.3	ENSP00000501530

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152124 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00642

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0127 AC: 3187 AN: 251122 Hom.: 37 AF XY: 0.0143 AC XY: 1935 AN XY: 135724

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00571

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.00634

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0133 AC: 19489 AN: 1461806 Hom.: 163 Cov.: 30 AF XY: 0.0140 AC XY: 10212 AN XY: 727190

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00691

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0236

Gnomad4 FIN exome AF: 0.00627

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.00983 AC: 1497 AN: 152242 Hom.: 15 Cov.: 33 AF XY: 0.00974 AC XY: 725 AN XY: 74440

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00955

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00642

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0137 Hom.: 23

Bravo AF: 0.00989

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0136 AC: 117

ExAC AF: 0.0137 AC: 1661

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0152

EpiControl AF: 0.0163

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	This variant is associated with the following publications: (PMID: 23804577) -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.093
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.32	T;T
Vest4		0.38
MPC		0.60
ClinPred		0.019	T
GERP RS		5.1
gMVP		0.31

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: rs61750217; hg19: chr21-34003786; COSMIC: COSV99050430; COSMIC: COSV99050430;