NM_006950.3:c.371C>T

Variant names:

• chrX-47619358-G-A
• rs1339768860
• NM_006950.3:c.371C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_006950.3(SYN1):​c.371C>T​(p.Thr124Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000921 in 1,086,269 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000092 (0 hom. 2 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.46
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31314594).
• BP6: Variant X-47619358-G-A is Benign according to our data. Variant chrX-47619358-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 499415.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.371C>T	p.Thr124Ile	missense	Exon 1 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.371C>T	p.Thr124Ile	missense	Exon 1 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.371C>T	p.Thr124Ile	missense	Exon 1 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.371C>T	p.Thr124Ile	missense	Exon 1 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.371C>T	p.Thr124Ile	missense	Exon 1 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000445 AC: 7 AN: 157162 AF XY: 0.0000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000921 AC: 10 AN: 1086269 Hom.: 0 Cov.: 31 AF XY: 0.00000558 AC XY: 2 AN XY: 358167

African (AFR) AF: 0.00 AC: 0 AN: 26300

American (AMR) AF: 0.000257 AC: 9 AN: 35002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30098

South Asian (SAS) AF: 0.00 AC: 0 AN: 53481

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2898

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840790

Other (OTH) AF: 0.00 AC: 0 AN: 45737

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

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 provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.85	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.18
Sift	Benign	0.061	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.45	B
Vest4		0.46
MutPred		0.64		Gain of methylation at K128 (P = 0.0502)
MVP		0.35
MPC		1.4
ClinPred		0.36	T
GERP RS		4.0
PromoterAI		0.039	Neutral
Varity_R		0.52
gMVP		0.81
Mutation Taster		=99/1	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: rs1339768860; hg19: chrX-47478757;