chrX-47574336-C-T

Position:

• chrX-47574336-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006950.3(SYN1):​c.1648G>A​(p.Ala550Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,042,104 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 2 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16033694).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1648G>A	p.Ala550Thr	missense_variant	12/13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1648G>A	p.Ala550Thr	missense_variant	12/13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1648G>A	p.Ala550Thr	missense_variant	12/13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1648G>A	p.Ala550Thr	missense_variant	12/13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.70+352G>A		intron_variant		5		ENSP00000492857.1

Frequencies

GnomAD3 genomes AF: 0.0000455 AC: 5 AN: 109930 Hom.: 0 Cov.: 23 AF XY: 0.0000303 AC XY: 1 AN XY: 32954

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: 0.0000962

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000225 AC: 21 AN: 932174 Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 2 AN XY: 290248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000256

GnomAD4 genome AF: 0.0000455 AC: 5 AN: 109930 Hom.: 0 Cov.: 23 AF XY: 0.0000303 AC XY: 1 AN XY: 32954

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000962

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 26, 2023	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. Experimental studies have shown that this missense change affects SYN1 function (PMID: 21441247, 26173895). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 41889). This variant is also known as p.Ala548Thr. This missense change has been observed in individuals with SYN1-related conditions (PMID: 21441247; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 550 of the SYN1 protein (p.Ala550Thr). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2011	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 15, 2023

Variant summary: SYN1 c.1648G>A (p.Ala550Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 17090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1648G>A has been reported in the literature in individuals affected with epilepsy, autism spectrum disorder, and schizophrenia (examples: Fassio_2011, and Mojarad_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders. Experimental studies have reported the variant affects normal protein function however is insufficient to determine the role of this variant in disease (examples: Fassio_2011, and Tang_2014). The following publications have been ascertained in the context of this evaluation (PMID: 21441247, 33526774, 26173895). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

SYN1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

The SYN1 c.1648G>A variant is predicted to result in the amino acid substitution p.Ala550Thr. This variant has been reported to be causative for autism spectrum disorders with or without epilepsy in four unrelated French Canadian patients (Fassio et al. 2011 et al. PubMed ID: 21441247). Functional studies showed that this variant displayed impaired targeting to nerve terminals (Fassio et al. 2011 et al. PubMed ID: 21441247; Tang et al. 2015. PubMed ID: 26173895, reported as A548T). This variant has not been reported in a large population database, indicating this variant is rare. However, it has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41889/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.64	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.15
Sift	Benign	0.28	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.43	B;P
Vest4		0.71
MutPred		0.32		Gain of phosphorylation at A550 (P = 0.0062);Gain of phosphorylation at A550 (P = 0.0062);
MVP		0.75
MPC		2.4
ClinPred		0.57	D
GERP RS		4.5
Varity_R		0.082
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514680; hg19: chrX-47433735;