X-47574012-G-A

Position:

• chrX-47574012-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006950.3(SYN1):​c.1972C>T​(p.Pro658Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000097 in 1,030,538 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: not found (cov: 24)
  • Exomes 𝑓: 9.7e-7 (0 hom. 1 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.81

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3620747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1972C>T	p.Pro658Ser	missense_variant	12/13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1972C>T	p.Pro658Ser	missense_variant	12/13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1972C>T	p.Pro658Ser	missense_variant	12/13	2	NM_006950.3	ENSP00000295987	P3
SYN1	ENST00000340666.5	c.1972C>T	p.Pro658Ser	missense_variant	12/13	1		ENSP00000343206	A1
SYN1	ENST00000640721.1	c.70+676C>T		intron_variant		5		ENSP00000492857

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.70e-7 AC: 1 AN: 1030538 Hom.: 0 Cov.: 32 AF XY: 0.00000303 AC XY: 1 AN XY: 330574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000382

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ExAC AF: 0.0000211 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 658 of the SYN1 protein (p.Pro658Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of SYN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 954219). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Intellectual disability, X-linked 50;C5774177:Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 07, 2022

This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:954219). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.97	D;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;T
Polyphen		0.98	D;D
Vest4		0.40
MutPred		0.28		Gain of phosphorylation at P658 (P = 0.0501);Gain of phosphorylation at P658 (P = 0.0501);
MVP		0.77
MPC		2.6
ClinPred		0.91	D
GERP RS		3.8
Varity_R		0.59
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs755832757; hg19: chrX-47433411;