rs760401568

Variant names:

• chrX-47577459-C-T
• rs760401568
• NM_006950.3:c.817G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_006950.3(SYN1):​c.817G>A​(p.Ala273Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000731 in 1,093,767 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000073 (0 hom. 4 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49
• Publications: 4 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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857
• BS2: High Hemizygotes in GnomAdExome4 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.817G>A	p.Ala273Thr	missense	Exon 6 of 13	NP_008881.2
	SYN1	NM_133499.2		c.817G>A	p.Ala273Thr	missense	Exon 6 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.817G>A	p.Ala273Thr	missense	Exon 6 of 13	ENSP00000295987.7
	SYN1	ENST00000340666.5	TSL:1	c.817G>A	p.Ala273Thr	missense	Exon 6 of 13	ENSP00000343206.4
	ENSG00000283743	ENST00000638776.2	TSL:5	n.3273G>A		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000580 AC: 1 AN: 172299 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: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000731 AC: 8 AN: 1093767 Hom.: 0 Cov.: 30 AF XY: 0.0000111 AC XY: 4 AN XY: 359853

African (AFR) AF: 0.00 AC: 0 AN: 26267

American (AMR) AF: 0.00 AC: 0 AN: 34857

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19265

East Asian (EAS) AF: 0.00 AC: 0 AN: 29977

South Asian (SAS) AF: 0.00 AC: 0 AN: 53170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40243

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000952 AC: 8 AN: 839907

Other (OTH) AF: 0.00 AC: 0 AN: 45949

GnomAD4 genome Cov.: 21

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.97	D
Vest4		0.60
MutPred		0.91		Gain of methylation at K269 (P = 0.0514)
MVP		0.60
MPC		1.4
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.49
gMVP		0.94
Mutation Taster		=75/25	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: rs760401568; hg19: chrX-47436858; COSMIC: COSV54482968; COSMIC: COSV54482968;