X-47574771-G-T

Variant names:

• chrX-47574771-G-T
• rs895517774
• NM_006950.3:c.1310C>A

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.1310C>A​(p.Pro437Gln) 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. 12/21 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. P437L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (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: 0.524
• 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=0.09377375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1310C>A	p.Pro437Gln	missense_variant	Exon 11 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1310C>A	p.Pro437Gln	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.1310C>A	p.Pro437Gln	missense_variant	Exon 11 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1310C>A	p.Pro437Gln	missense_variant	Exon 11 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.-14C>A		upstream_gene_variant		5		ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1070987 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 347631

African (AFR) AF: 0.00 AC: 0 AN: 26191

American (AMR) AF: 0.00 AC: 0 AN: 30098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18784

East Asian (EAS) AF: 0.00 AC: 0 AN: 29405

South Asian (SAS) AF: 0.00 AC: 0 AN: 50995

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3882

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828015

Other (OTH) AF: 0.00 AC: 0 AN: 45090

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Uncertain:1

Jun 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SYN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 437 of the SYN1 protein (p.Pro437Gln).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;.
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PhyloP100		0.52
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Benign	0.031
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.014	D;T
Vest4		0.15
ClinPred		0.12	T
GERP RS		2.4
PromoterAI		0.071	Neutral
Varity_R		0.12
gMVP		0.26
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs895517774; hg19: chrX-47434170;