rs748323076

chrX-47574712-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006950.3(SYN1):c.1369G>C(p.Ala457Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,184,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A457D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 4 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042538762).
• BP6: Variant X-47574712-C-G is Benign according to our data. Variant chrX-47574712-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 465089.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.1369G>C	p.Ala457Pro	missense_variant	11/13	ENST00000295987.13
SYN1	NM_133499.2	c.1369G>C	p.Ala457Pro	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13	c.1369G>C	p.Ala457Pro	missense_variant	11/13	2	NM_006950.3	P3
SYN1	ENST00000340666.5	c.1369G>C	p.Ala457Pro	missense_variant	11/13	1		A1
SYN1	ENST00000640721.1	c.46G>C	p.Ala16Pro	missense_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 18 AN: 111563 Hom.: 0 Cov.: 23 AF XY: 0.000148 AC XY: 5 AN XY: 33875

Gnomad AFR AF: 0.000554

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000932

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000234 AC: 3 AN: 128058 Hom.: 0 AF XY: 0.0000241 AC XY: 1 AN XY: 41430

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000112 AC: 12 AN: 1072833 Hom.: 0 Cov.: 31 AF XY: 0.0000114 AC XY: 4 AN XY: 349941

Gnomad4 AFR exome AF: 0.000381

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000161 AC: 18 AN: 111563 Hom.: 0 Cov.: 23 AF XY: 0.000148 AC XY: 5 AN XY: 33875

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.0000932

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.0000535 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	23
Dann	Benign	0.91
DEOGEN2	Benign	0.20	T;.;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.49	T;T;.
Polyphen		0.98	D;D;.
Vest4		0.35
MVP		0.44
MPC		0.87
ClinPred		0.074	T
GERP RS		4.3
Varity_R		0.39
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs748323076; hg19: chrX-47434111;