rs377385507

Positions:

• chrX-47576240-AGACAAAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006950.3(SYN1):​c.1056-14_1056-8delCTTTGTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,200,263 control chromosomes in the GnomAD database, including 11 homozygotes. There are 385 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., 174 hem., cov: 23)
  • Exomes 𝑓: 0.00070 (8 hom. 211 hem.)
• Consequence: SYN1 NM_006950.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.09

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]

ENSG00000283743 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-47576240-AGACAAAG-A is Benign according to our data. Variant chrX-47576240-AGACAAAG-A is described in ClinVar as [Benign]. Clinvar id is 199183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47576240-AGACAAAG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00574 (646/112452) while in subpopulation AFR AF= 0.0194 (600/30967). AF 95% confidence interval is 0.0181. There are 3 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1056-14_1056-8delCTTTGTC		splice_region_variant, intron_variant		ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1056-14_1056-8delCTTTGTC		splice_region_variant, intron_variant			NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1056-14_1056-8delCTTTGTC		splice_region_variant, intron_variant		2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1056-14_1056-8delCTTTGTC		splice_region_variant, intron_variant		1		ENSP00000343206.4
ENSG00000283743	ENST00000638776.2	n.3512-14_3512-8delCTTTGTC		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00569 AC: 640 AN: 112397 Hom.: 3 Cov.: 23 AF XY: 0.00489 AC XY: 169 AN XY: 34545

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

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: 0.0000376

Gnomad OTH AF: 0.00596

GnomAD3 exomes AF: 0.00176 AC: 281 AN: 159843 Hom.: 5 AF XY: 0.00107 AC XY: 53 AN XY: 49683

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000240

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000435

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000700 AC: 762 AN: 1087811 Hom.: 8 AF XY: 0.000594 AC XY: 211 AN XY: 355325

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000239

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00574 AC: 646 AN: 112452 Hom.: 3 Cov.: 23 AF XY: 0.00503 AC XY: 174 AN XY: 34610

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.00328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00589

Alfa AF: 0.00278 Hom.: 7

Bravo AF: 0.00733

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

SYN1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 11, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377385507; hg19: chrX-47435639;