X-47572939-G-A

Variant names:

• chrX-47572939-G-A
• rs917416561
• ENST00000340666.5:c.2005C>T

Variant summary

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

The NM_133499.2(SYN1):​c.2005C>T​(p.Pro669Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P669T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SYN1 NM_133499.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, G2P
• intellectual disability, X-linked 50

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia

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=0.19218919).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133499.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.2043C>T	p.Ser681Ser	synonymous	Exon 13 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.2005C>T	p.Pro669Ser	missense	Exon 13 of 13	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000340666.5	TSL:1	c.2005C>T	p.Pro669Ser	missense	Exon 13 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.2043C>T	p.Ser681Ser	synonymous	Exon 13 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000950906.1		c.2040C>T	p.Ser680Ser	synonymous	Exon 13 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.2
PROVEAN	Benign	0.060	N
REVEL	Benign	0.049
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.52	P
Vest4		0.32
MutPred		0.32		Gain of phosphorylation at P669 (P = 0.0276)
MVP		0.46
ClinPred		0.84	D
GERP RS		4.8
Mutation Taster		=83/17	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: rs917416561; hg19: chrX-47432338;