X-47574714-G-C

Variant names:

• chrX-47574714-G-C
• rs769924948
• NM_006950.3:c.1367C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006950.3(SYN1):​c.1367C>G​(p.Pro456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41
• Publications: 0 publications found

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

ACMG classification

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=0.23603621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1367C>G	p.Pro456Arg	missense_variant	Exon 11 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1367C>G	p.Pro456Arg	missense_variant	Exon 11 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1367C>G	p.Pro456Arg	missense_variant	Exon 11 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1367C>G	p.Pro456Arg	missense_variant	Exon 11 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.44C>G	p.Pro15Arg	missense_variant	Exon 1 of 2	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111867 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1071212 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 348494

African (AFR) AF: 0.00 AC: 0 AN: 26174

American (AMR) AF: 0.00 AC: 0 AN: 29917

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18754

East Asian (EAS) AF: 0.00 AC: 0 AN: 29262

South Asian (SAS) AF: 0.00 AC: 0 AN: 50942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3856

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828719

Other (OTH) AF: 0.00 AC: 0 AN: 45095

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111867 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34091

African (AFR) AF: 0.00 AC: 0 AN: 30772

American (AMR) AF: 0.00 AC: 0 AN: 10773

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52955

Other (OTH) AF: 0.00 AC: 0 AN: 1501

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D;.;.
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;N;.
PhyloP100		3.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	N;D;.
REVEL	Benign	0.050
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0090	D;D;.
Polyphen		0.0	B;B;.
Vest4		0.28
MutPred		0.39		Gain of MoRF binding (P = 0.0078);Gain of MoRF binding (P = 0.0078);.;
MVP		0.14
MPC		0.97
ClinPred		0.50	T
GERP RS		4.3
PromoterAI		0.013	Neutral
Varity_R		0.22
gMVP		0.32
Mutation Taster		=87/13	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

Other links and lift over

dbSNP: rs769924948; hg19: chrX-47434113;