rs200533370

Variant names:

• chrX-47574285-T-C
• rs200533370
• NM_006950.3:c.1699A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006950.3(SYN1):​c.1699A>G​(p.Thr567Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,101,774 control chromosomes in the GnomAD database, including 48 homozygotes. There are 755 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T567T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., 427 hem., cov: 24)
  • Exomes 𝑓: 0.0012 (24 hom. 328 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: -0.218
• Publications: 15 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00393793).
• BP6: Variant X-47574285-T-C is Benign according to our data. Variant chrX-47574285-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41890.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (1506/111841) while in subpopulation AFR AF = 0.0468 (1442/30814). AF 95% confidence interval is 0.0448. There are 24 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.1699A>G	p.Thr567Ala	missense	Exon 12 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1699A>G	p.Thr567Ala	missense	Exon 12 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.1699A>G	p.Thr567Ala	missense	Exon 12 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1699A>G	p.Thr567Ala	missense	Exon 12 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1696A>G	p.Thr566Ala	missense	Exon 12 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 1505 AN: 111798 Hom.: 24 Cov.: 24

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00343

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.000303

Gnomad OTH AF: 0.00597

GnomAD2 exomes AF: 0.00113 AC: 61 AN: 53883 AF XY: 0.000326

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00122 AC: 1212 AN: 989933 Hom.: 24 Cov.: 32 AF XY: 0.00103 AC XY: 328 AN XY: 318907

African (AFR) AF: 0.0474 AC: 997 AN: 21036

American (AMR) AF: 0.00229 AC: 48 AN: 20963

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17017

East Asian (EAS) AF: 0.00 AC: 0 AN: 21841

South Asian (SAS) AF: 0.0000454 AC: 2 AN: 44038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25072

Middle Eastern (MID) AF: 0.00330 AC: 9 AN: 2731

European-Non Finnish (NFE) AF: 0.0000566 AC: 45 AN: 795551

Other (OTH) AF: 0.00266 AC: 111 AN: 41684

GnomAD4 genome AF: 0.0135 AC: 1506 AN: 111841 Hom.: 24 Cov.: 24 AF XY: 0.0125 AC XY: 427 AN XY: 34295

African (AFR) AF: 0.0468 AC: 1442 AN: 30814

American (AMR) AF: 0.00333 AC: 36 AN: 10812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3463

South Asian (SAS) AF: 0.00 AC: 0 AN: 2761

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6136

Middle Eastern (MID) AF: 0.0142 AC: 3 AN: 211

European-Non Finnish (NFE) AF: 0.000303 AC: 16 AN: 52805

Other (OTH) AF: 0.00589 AC: 9 AN: 1528

Alfa AF: 0.00626 Hom.: 41

Bravo AF: 0.0151

ExAC AF: 0.00137 AC: 68

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	3	not specified (4)
-	-	2	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (2)
-	-	1	History of neurodevelopmental disorder (1)
-	1	-	Intellectual disability, X-linked 50 (1)
-	-	1	SYN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.22
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.27
Sift	Benign	0.43	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.66
MVP		0.92
MPC		2.0
ClinPred		0.0060	T
GERP RS		0.73
PromoterAI		-0.098	Neutral
Varity_R		0.039
gMVP		0.21
Mutation Taster		=90/10	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: rs200533370; hg19: chrX-47433684; COSMIC: COSV55983533; COSMIC: COSV55983533;