X-47572954-G-A

Position:

• chrX-47572954-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The ENST00000340666.5(SYN1):​c.1990C>T​(p.Pro664Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,153 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P664P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: SYN1 ENST00000340666.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1
• Conservation: PhyloP100: 1.26

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 -4 ACMG points.

• PP5: Variant X-47572954-G-A is Pathogenic according to our data. Variant chrX-47572954-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 862372.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11893743). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.2028C>T	p.Ala676=	synonymous_variant	13/13	ENST00000295987.13
SYN1	NM_133499.2	c.1990C>T	p.Pro664Ser	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000340666.5	c.1990C>T	p.Pro664Ser	missense_variant	13/13	1		A1
SYN1	ENST00000295987.13	c.2028C>T	p.Ala676=	synonymous_variant	13/13	2	NM_006950.3	P3
SYN1	ENST00000640721.1	c.78C>T	p.Ala26=	synonymous_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098153 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363513

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 862372). This missense change has been observed in individual(s) with clinical features of SYN1-related condition (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 664 of the SYN1 protein (p.Pro664Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.91
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Polyphen		0.017	B
Vest4		0.21
MutPred		0.22		Gain of phosphorylation at P664 (P = 0.0225);
MVP		0.57
ClinPred		0.24	T
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2057764630; hg19: chrX-47432353;