chrX-47574760-C-T

Variant names:

• chrX-47574760-C-T
• rs772106134
• NM_006950.3:c.1321G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006950.3(SYN1):​c.1321G>A​(p.Ala441Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000027 in 1,073,470 control chromosomes in the GnomAD database, including 1 homozygotes. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A441S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000027 (1 hom. 14 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.23
• 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05308047).
• BS2: High Hemizygotes in GnomAdExome4 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.1321G>A	p.Ala441Thr	missense	Exon 11 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1321G>A	p.Ala441Thr	missense	Exon 11 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.1321G>A	p.Ala441Thr	missense	Exon 11 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1321G>A	p.Ala441Thr	missense	Exon 11 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1318G>A	p.Ala440Thr	missense	Exon 11 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000764 AC: 1 AN: 130933 AF XY: 0.0000235

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000270 AC: 29 AN: 1073470 Hom.: 1 Cov.: 31 AF XY: 0.0000400 AC XY: 14 AN XY: 349620

African (AFR) AF: 0.00 AC: 0 AN: 26231

American (AMR) AF: 0.00 AC: 0 AN: 30252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18801

East Asian (EAS) AF: 0.00 AC: 0 AN: 29430

South Asian (SAS) AF: 0.000528 AC: 27 AN: 51111

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38639

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3862

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 829973

Other (OTH) AF: 0.0000443 AC: 2 AN: 45171

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000444 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.021
Sift	Benign	0.28	T
Sift4G	Benign	0.41	T
Polyphen		0.010	B
Vest4		0.084
MutPred		0.30		Loss of loop (P = 0.0203)
MVP		0.27
MPC		0.66
ClinPred		0.24	T
GERP RS		4.5
PromoterAI		-0.057	Neutral
Varity_R		0.13
gMVP		0.15
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: rs772106134; hg19: chrX-47434159;