Genetic Variant SYN1:p.Thr567Thr (chrX-47574283-T-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_006950.3(SYN1):c.1701A>C(p.Thr567Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 990,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T567T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Consequence

SYN1
NM_006950.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.364

Publications

0 publications found

Variant links:

Genes affected

SYN1 (HGNC:11494): (synapsin I) This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

SYN1 Gene-Disease associations (from GenCC):

X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
epilepsy, X-linked 1, with variable learning disabilities and behavior disorders
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

SYN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP7

Synonymous conserved (PhyloP=-0.364 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.1701A>C	p.Thr567Thr	synonymous_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2 link	c.1701A>C	p.Thr567Thr	synonymous_variant	Exon 12 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYN1	ENST00000295987.13 link	c.1701A>C	p.Thr567Thr	synonymous_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5 link	c.1701A>C	p.Thr567Thr	synonymous_variant	Exon 12 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1 link	c.70+405A>C		intron_variant	Intron 1 of 1	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000101

AC:

AN:

990437

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

319217

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21065

American (AMR)

AF:

0.00

AC:

AN:

21072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17029

East Asian (EAS)

AF:

0.00

AC:

AN:

21854

South Asian (SAS)

AF:

0.00

AC:

AN:

44122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2734

European-Non Finnish (NFE)

AF:

0.00000126

AC:

AN:

795777

Other (OTH)

AF:

0.00

AC:

AN:

41702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.4

(source)

DANN

Benign

0.67

PhyloP100

-0.36

PromoterAI

-0.14

Neutral

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over