rs41298474

Variant names:

• chrX-47575136-G-A
• rs41298474
• NM_006950.3:c.1297C>T

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.1297C>T​(p.His433Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,187,985 control chromosomes in the GnomAD database, including 5 homozygotes. There are 139 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 14 hem., cov: 24)
  • Exomes 𝑓: 0.00039 (5 hom. 125 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 1.35
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062771738).
• BP6: Variant X-47575136-G-A is Benign according to our data. Variant chrX-47575136-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207470.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000394 (424/1075157) while in subpopulation AMR AF = 0.00201 (64/31850). AF 95% confidence interval is 0.00161. There are 5 homozygotes in GnomAdExome4. There are 125 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 14 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.1297C>T	p.His433Tyr	missense	Exon 10 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1297C>T	p.His433Tyr	missense	Exon 10 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.1297C>T	p.His433Tyr	missense	Exon 10 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1297C>T	p.His433Tyr	missense	Exon 10 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1294C>T	p.His432Tyr	missense	Exon 10 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes AF: 0.000399 AC: 45 AN: 112773 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000463

Gnomad ASJ AF: 0.0117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.00124 AC: 175 AN: 140579 AF XY: 0.000965

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00455

GnomAD4 exome AF: 0.000394 AC: 424 AN: 1075157 Hom.: 5 Cov.: 32 AF XY: 0.000357 AC XY: 125 AN XY: 350147

African (AFR) AF: 0.00 AC: 0 AN: 25795

American (AMR) AF: 0.00201 AC: 64 AN: 31850

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 259 AN: 18951

East Asian (EAS) AF: 0.00 AC: 0 AN: 28769

South Asian (SAS) AF: 0.00 AC: 0 AN: 51232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3838

European-Non Finnish (NFE) AF: 0.0000457 AC: 38 AN: 830677

Other (OTH) AF: 0.00140 AC: 63 AN: 45149

GnomAD4 genome AF: 0.000399 AC: 45 AN: 112828 Hom.: 0 Cov.: 24 AF XY: 0.000400 AC XY: 14 AN XY: 34982

African (AFR) AF: 0.00 AC: 0 AN: 31132

American (AMR) AF: 0.000462 AC: 5 AN: 10813

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 31 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2775

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6272

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

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53192

Other (OTH) AF: 0.00195 AC: 3 AN: 1538

Alfa AF: 0.000775 Hom.: 38

Bravo AF: 0.000620

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000894 AC: 6

ExAC AF: 0.000852 AC: 101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (2)
-	1	1	not provided (2)
-	-	1	SYN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.062
Sift	Benign	0.46	T
Sift4G	Benign	0.88	T
Polyphen		0.96	D
Vest4		0.23
MVP		0.26
MPC		1.2
ClinPred		0.067	T
GERP RS		5.0
PromoterAI		0.0012	Neutral
Varity_R		0.22
gMVP		0.52
Mutation Taster		=96/4	disease causing (ClinVar)

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: rs41298474; hg19: chrX-47434535;