Genetic Variant NM_203446.3:c.199C>A (chr21-32701973-G-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_203446.3(SYNJ1):c.199C>A(p.Arg67Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,391,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

SYNJ1
NM_203446.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.27

Publications

0 publications found

Variant links:

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
early-onset Parkinson disease 20
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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

SYNJ1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP7

Synonymous conserved (PhyloP=3.27 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3 link	c.199C>A	p.Arg67Arg	synonymous_variant	Exon 3 of 33	ENST00000674351.1	NP_982271.3	O43426-2C9JFZ1Q05CZ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1 link	c.199C>A	p.Arg67Arg	synonymous_variant	Exon 3 of 33		NM_203446.3	ENSP00000501530.1		O43426-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1391960

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685544

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32418

American (AMR)

AF:

0.00

AC:

AN:

41708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24474

East Asian (EAS)

AF:

0.00

AC:

AN:

38562

South Asian (SAS)

AF:

0.00

AC:

AN:

72846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1068200

Other (OTH)

AF:

0.00

AC:

AN:

56944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.048241), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

3.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over