rs769458536

Variant names:

• chrX-47606946-G-A
• rs769458536
• NM_006950.3:c.526C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS2

The NM_006950.3(SYN1):​c.526C>T​(p.Arg176Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,204,617 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., 4 hem., cov: 20)
  • Exomes 𝑓: 0.000017 (0 hom. 5 hem.)
• Consequence: SYN1 NM_006950.3 missense, splice_region
• Scores: Splicing: ADA: 0.02639
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.87
• Publications: 0 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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• BP6: Variant X-47606946-G-A is Benign according to our data. Variant chrX-47606946-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207466.
• BS2: High Hemizygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.526C>T	p.Arg176Trp	missense splice_region	Exon 3 of 13	NP_008881.2
	SYN1	NM_133499.2		c.526C>T	p.Arg176Trp	missense splice_region	Exon 3 of 13	NP_598006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.526C>T	p.Arg176Trp	missense splice_region	Exon 3 of 13	ENSP00000295987.7
	SYN1	ENST00000340666.5	TSL:1	c.526C>T	p.Arg176Trp	missense splice_region	Exon 3 of 13	ENSP00000343206.4
	SYN1	ENST00000639776.1	TSL:3	c.184C>T	p.Arg62Trp	missense splice_region	Exon 3 of 6	ENSP00000492521.1

Frequencies

GnomAD3 genomes AF: 0.0000916 AC: 10 AN: 109154 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000493

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000380

Gnomad OTH AF: 0.00207

GnomAD2 exomes AF: 0.0000385 AC: 7 AN: 181606 AF XY: 0.0000753

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000743

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1095463 Hom.: 0 Cov.: 28 AF XY: 0.0000139 AC XY: 5 AN XY: 360925

African (AFR) AF: 0.0000379 AC: 1 AN: 26355

American (AMR) AF: 0.0000853 AC: 3 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19356

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53981

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 839922

Other (OTH) AF: 0.0000652 AC: 3 AN: 45993

GnomAD4 genome AF: 0.0000916 AC: 10 AN: 109154 Hom.: 0 Cov.: 20 AF XY: 0.000127 AC XY: 4 AN XY: 31486

African (AFR) AF: 0.00 AC: 0 AN: 29815

American (AMR) AF: 0.000493 AC: 5 AN: 10137

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5601

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000380 AC: 2 AN: 52579

Other (OTH) AF: 0.00207 AC: 3 AN: 1451

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.84		Loss of ubiquitination at K179 (P = 0.0527)
MVP		0.88
MPC		1.0
ClinPred		0.77	D
GERP RS		2.8
Varity_R		0.78
gMVP		0.88
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.026
dbscSNV1_RF	Benign	0.10
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: rs769458536; hg19: chrX-47466345; COSMIC: COSV105163322;