21-32631044-G-A

Variant names:

• chr21-32631044-G-A
• rs111516740
• ENST00000433931.7:c.4790C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003895.4(SYNJ1):​c.4790C>T​(p.Thr1597Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,100 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T1597T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (4 hom.)
• Consequence: SYNJ1 NM_003895.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.981

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056349933).
• BP6: Variant 21-32631044-G-A is Benign according to our data. Variant chr21-32631044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00137 (208/152286) while in subpopulation AFR AF = 0.00464 (193/41562). AF 95% confidence interval is 0.00411. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.*761C>T		3_prime_UTR_variant	Exon 33 of 33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351	c.*761C>T		3_prime_UTR_variant	Exon 33 of 33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152168 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000323 AC: 81 AN: 251154 AF XY: 0.000265

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461814 Hom.: 4 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 727212

Gnomad4 AFR exome AF: 0.00356 AC: 119 AN: 33472

Gnomad4 AMR exome AF: 0.0000894 AC: 4 AN: 44720

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26124

Gnomad4 EAS exome AF: 0.000554 AC: 22 AN: 39700

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86250

Gnomad4 FIN exome AF: 0.000150 AC: 8 AN: 53404

Gnomad4 NFE exome AF: 0.0000450 AC: 50 AN: 1111980

Gnomad4 Remaining exome AF: 0.000563 AC: 34 AN: 60396

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74466

Gnomad4 AFR AF: 0.00464 AC: 0.00464366 AN: 0.00464366

Gnomad4 AMR AF: 0.000196 AC: 0.000196027 AN: 0.000196027

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000193199 AN: 0.000193199

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000283 AC: 0.000282592 AN: 0.000282592

Gnomad4 NFE AF: 0.0000735 AC: 0.0000735078 AN: 0.0000735078

Gnomad4 OTH AF: 0.00142 AC: 0.0014218 AN: 0.0014218

Alfa AF: 0.000483 Hom.: 0

Bravo AF: 0.00138

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SYNJ1-related disorder Uncertain:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SYNJ1 c.4790C>T variant is predicted to result in the amino acid substitution p.Thr1597Met. This variant has been reported in the heterozygous state in a cohort of patient with early onset Parkinson's disease (Supplementary Table 12, Chen et al. 2022. PubMed ID: 35861376). This variant is reported in 0.45% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.024
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.022	D;D
Vest4		0.34
MVP		0.36
MPC		0.38
ClinPred		0.031	T
GERP RS		3.6
gMVP		0.24
Mutation Taster		=95/5	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

Publications

LitVar

Other links and lift over

dbSNP: rs111516740; hg19: chr21-34003354; COSMIC: COSV105227894; COSMIC: COSV105227894;