rs147929290

Positions:

• chr21-32665968-A-G

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 9.32

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 -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 id is 544560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ1	NM_203446.3	c.2120T>C	p.Ile707Thr	missense_variant	17/33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1	c.2120T>C	p.Ile707Thr	missense_variant	17/33		NM_203446.3	ENSP00000501530.1

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

GnomAD3 exomes AF: 0.000894 AC: 222 AN: 248188 Hom.: 0 AF XY: 0.000962 AC XY: 129 AN XY: 134116

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 SAS 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

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00156

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

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00121 Hom.: 1

Bravo AF: 0.000759

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.000972 AC: 118

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SYNJ1: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31592138) -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;.;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.55	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D;D;.;D;D
REVEL	Pathogenic	0.90
Sift	Benign	0.099	T;T;.;T;T
Sift4G	Benign	0.076	T;T;T;T;T
Polyphen		1.0	D;.;.;P;.
Vest4		0.97
MVP		0.97
MPC		1.7
ClinPred		0.20	T
GERP RS		6.0
gMVP		0.93

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: rs147929290; hg19: chr21-34038278; COSMIC: COSV105227913; COSMIC: COSV105227913;