rs187134574

chrX-47619577-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006950.3(SYN1):c.152C>G(p.Ala51Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,165,532 control chromosomes in the GnomAD database, including 42 homozygotes. There are 670 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., 356 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (16 hom. 314 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.64

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026123822).
• BP6: Variant X-47619577-G-C is Benign according to our data. Variant chrX-47619577-G-C is described in ClinVar as [Benign]. Clinvar id is 139384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47619577-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1361/111764) while in subpopulation AFR AF= 0.0423 (1302/30808). AF 95% confidence interval is 0.0404. There are 26 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.152C>G	p.Ala51Gly	missense_variant	1/13	ENST00000295987.13
SYN1	NM_133499.2	c.152C>G	p.Ala51Gly	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13	c.152C>G	p.Ala51Gly	missense_variant	1/13	2	NM_006950.3	P3
SYN1	ENST00000340666.5	c.152C>G	p.Ala51Gly	missense_variant	1/13	1		A1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1359 AN: 111715 Hom.: 26 Cov.: 22 AF XY: 0.0105 AC XY: 356 AN XY: 33951

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00469

GnomAD3 exomes AF: 0.00260 AC: 274 AN: 105205 Hom.: 4 AF XY: 0.00120 AC XY: 38 AN XY: 31795

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.00132

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: 0.0000764

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.00121 AC: 1280 AN: 1053768 Hom.: 16 Cov.: 31 AF XY: 0.000927 AC XY: 314 AN XY: 338668

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00161

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: 0.0000403

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.0122 AC: 1361 AN: 111764 Hom.: 26 Cov.: 22 AF XY: 0.0105 AC XY: 356 AN XY: 34010

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.00297

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00464

Alfa AF: 0.00705 Hom.: 40

Bravo AF: 0.0138

ESP6500AA AF: 0.0176 AC: 40

ESP6500EA AF: 0.000219 AC: 1

ExAC AF: 0.00250 AC: 250

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2018	This variant is associated with the following publications: (PMID: 23871722, 21441247, 27884173) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 19, 2016

- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.92	P;P
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.051
Sift	Benign	0.28	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0010	B;B
Vest4		0.66
MVP		0.34
MPC		0.80
ClinPred		0.0041	T
GERP RS		3.1
Varity_R		0.096
gMVP		0.35

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: rs187134574; hg19: chrX-47478976;