rs12394306

Variant names:

• chrX-47576648-A-C
• rs12394306
• NM_006950.3:c.838-8T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-47576648-A-C
• chrX-47576648-A-T

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0009189
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.876
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, G2P
• intellectual disability, X-linked 50

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006950.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.838-8T>G		splice_region intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.838-8T>G		splice_region intron	N/A	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.838-8T>G		splice_region intron	N/A	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.838-8T>G		splice_region intron	N/A	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.838-8T>G		splice_region intron	N/A	ENSP00000620965.1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 1626 AN: 111802 Hom.: 26 Cov.: 22

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

GnomAD2 exomes AF: 0.00425 AC: 777 AN: 182614 AF XY: 0.00278

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 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

African (AFR) AF: 0.0499 AC: 1316 AN: 26394

American (AMR) AF: 0.00386 AC: 136 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.000388 AC: 21 AN: 54124

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40517

Middle Eastern (MID) AF: 0.00256 AC: 10 AN: 3910

European-Non Finnish (NFE) AF: 0.0000677 AC: 57 AN: 842116

Other (OTH) AF: 0.00549 AC: 253 AN: 46068

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

African (AFR) AF: 0.0501 AC: 1540 AN: 30712

American (AMR) AF: 0.00662 AC: 70 AN: 10576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2707

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6098

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53139

Other (OTH) AF: 0.0118 AC: 18 AN: 1525

Alfa AF: 0.00485 Hom.: 200

Bravo AF: 0.0175

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.70
DANN	Benign	0.66
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12394306; hg19: chrX-47436047;