rs12394306

chrX-47576648-A-CchrX-47576648-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006950.3(SYN1):c.838-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,209,775 control chromosomes in the GnomAD database, including 65 homozygotes. There are 926 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (26 hom., 443 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (39 hom. 483 hem.)
• Consequence: SYN1 NM_006950.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009189
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.876

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-47576648-A-C is Benign according to our data. Variant chrX-47576648-A-C is described in ClinVar as [Benign]. Clinvar id is 130385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (1636/111856) while in subpopulation AFR AF= 0.0501 (1540/30712). AF 95% confidence interval is 0.0481. There are 26 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.838-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000295987.13
SYN1	NM_133499.2	c.838-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13	c.838-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_006950.3	P3
SYN1	ENST00000340666.5	c.838-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 1626 AN: 111802 Hom.: 26 Cov.: 22 AF XY: 0.0128 AC XY: 435 AN XY: 33958

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000737

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00425 AC: 777 AN: 182614 Hom.: 16 AF XY: 0.00278 AC XY: 187 AN XY: 67166

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00163 AC: 1795 AN: 1097919 Hom.: 39 Cov.: 33 AF XY: 0.00133 AC XY: 483 AN XY: 363355

Gnomad4 AFR exome AF: 0.0499

Gnomad4 AMR exome AF: 0.00386

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000388

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.0000677

Gnomad4 OTH exome AF: 0.00549

GnomAD4 genome AF: 0.0146 AC: 1636 AN: 111856 Hom.: 26 Cov.: 22 AF XY: 0.0130 AC XY: 443 AN XY: 34022

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.00662

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000369

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00173 Hom.: 49

Bravo AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 30, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.70
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.060
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: rs12394306; hg19: chrX-47436047;