rs1085307749

Variant names:

• chrX-47576595-C-T
• rs1085307749
• NM_006950.3:c.883G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006950.3(SYN1):​c.883G>A​(p.Val295Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,098,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V295V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.11
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

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.883G>A	p.Val295Met	missense	Exon 7 of 13	NP_008881.2
	SYN1	NM_133499.2		c.883G>A	p.Val295Met	missense	Exon 7 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.883G>A	p.Val295Met	missense	Exon 7 of 13	ENSP00000295987.7
	SYN1	ENST00000340666.5	TSL:1	c.883G>A	p.Val295Met	missense	Exon 7 of 13	ENSP00000343206.4
	ENSG00000283743	ENST00000638776.2	TSL:5	n.3339G>A		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098160 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363516

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842076

Other (OTH) AF: 0.0000217 AC: 1 AN: 46093

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.029	D
Polyphen		0.97	D
Vest4		0.68
MutPred		0.67		Gain of ubiquitination at K299 (P = 0.095)
MVP		0.64
MPC		1.5
ClinPred		0.83	D
GERP RS		4.2
Varity_R		0.39
gMVP		0.94
Mutation Taster		=87/13	polymorphism

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: rs1085307749; hg19: chrX-47435994; COSMIC: COSV55980630; COSMIC: COSV55980630;