rs150248483

Variant names:

• chrX-47576182-G-A
• rs150248483
• NM_006950.3:c.1107C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006950.3(SYN1):​c.1107C>T​(p.Ile369Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,203,169 control chromosomes in the GnomAD database, including 1 homozygotes. There are 629 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 32 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (1 hom. 597 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 0.988
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-47576182-G-A is Benign according to our data. Variant chrX-47576182-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96363.
• BP7: Synonymous conserved (PhyloP=0.988 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00102 (114/112045) while in subpopulation NFE AF = 0.00188 (100/53152). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 32 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.1107C>T	p.Ile369Ile	synonymous	Exon 9 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1107C>T	p.Ile369Ile	synonymous	Exon 9 of 13	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.1107C>T	p.Ile369Ile	synonymous	Exon 9 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1107C>T	p.Ile369Ile	synonymous	Exon 9 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1104C>T	p.Ile368Ile	synonymous	Exon 9 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 114 AN: 111993 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00100 AC: 166 AN: 165485 AF XY: 0.000958

Gnomad AFR exome AF: 0.000169

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.000474

GnomAD4 exome AF: 0.00174 AC: 1894 AN: 1091124 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 597 AN XY: 357802

African (AFR) AF: 0.000305 AC: 8 AN: 26219

American (AMR) AF: 0.000145 AC: 5 AN: 34425

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19267

East Asian (EAS) AF: 0.00 AC: 0 AN: 29874

South Asian (SAS) AF: 0.00 AC: 0 AN: 52830

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 40065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00220 AC: 1846 AN: 838486

Other (OTH) AF: 0.000742 AC: 34 AN: 45828

GnomAD4 genome AF: 0.00102 AC: 114 AN: 112045 Hom.: 0 Cov.: 23 AF XY: 0.000935 AC XY: 32 AN XY: 34227

African (AFR) AF: 0.000259 AC: 8 AN: 30856

American (AMR) AF: 0.000470 AC: 5 AN: 10627

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.000165 AC: 1 AN: 6067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00188 AC: 100 AN: 53152

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00105 Hom.: 7

Bravo AF: 0.00104

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	1	not specified (2)
-	-	1	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.3
DANN	Benign	0.63
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs150248483; hg19: chrX-47435581;