Genetic Variant SYN1:p.Pro437Arg (chrX-47574771-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006950.3(SYN1):c.1310C>G(p.Pro437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000934 in 1,070,987 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P437Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.524

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1068418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.1310C>G	p.Pro437Arg	missense_variant	Exon 11 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2 link	c.1310C>G	p.Pro437Arg	missense_variant	Exon 11 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYN1	ENST00000295987.13 link	c.1310C>G	p.Pro437Arg	missense_variant	Exon 11 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5 link	c.1310C>G	p.Pro437Arg	missense_variant	Exon 11 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1 link	c.-14C>G		upstream_gene_variant		5		ENSP00000492857.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.34e-7

AC:

AN:

1070987

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

347631

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26191

American (AMR)

AF:

0.00

AC:

AN:

30098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18784

East Asian (EAS)

AF:

0.00

AC:

AN:

29406

South Asian (SAS)

AF:

0.00

AC:

AN:

50995

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3882

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

828014

Other (OTH)

AF:

0.00

AC:

AN:

45090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PhyloP100

0.52

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.027

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.060

T;T

Vest4

0.20

ClinPred

0.16

GERP RS

2.4

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.19

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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