X-47574040-G-A

Variant names:

• chrX-47574040-G-A
• rs1556857414
• NM_006950.3:c.1944C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_006950.3(SYN1):​c.1944C>T​(p.Ala648Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.10
• 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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-47574040-G-A is Benign according to our data. Variant chrX-47574040-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 465095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.1 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.1944C>T	p.Ala648Ala	synonymous	Exon 12 of 13	NP_008881.2
	SYN1	NM_133499.2		c.1944C>T	p.Ala648Ala	synonymous	Exon 12 of 13	NP_598006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.1944C>T	p.Ala648Ala	synonymous	Exon 12 of 13	ENSP00000295987.7
	SYN1	ENST00000340666.5	TSL:1	c.1944C>T	p.Ala648Ala	synonymous	Exon 12 of 13	ENSP00000343206.4
	SYN1	ENST00000640721.1	TSL:5	c.70+648C>T		intron	N/A	ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1038620 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 334394

African (AFR) AF: 0.00 AC: 0 AN: 24456

American (AMR) AF: 0.00 AC: 0 AN: 27493

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18133

East Asian (EAS) AF: 0.00 AC: 0 AN: 26711

South Asian (SAS) AF: 0.00 AC: 0 AN: 48972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29413

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2861

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 816679

Other (OTH) AF: 0.00 AC: 0 AN: 43902

GnomAD4 genome Cov.: 24

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

Apr 29, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1556857414; hg19: chrX-47433439;