X-47574355-A-G

Variant names:

• chrX-47574355-A-G
• rs1027134708
• NM_006950.3:c.1629T>C

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.1629T>C​(p.Pro543Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000109 in 917,869 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.82
• 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=-0.63).
• BP6: Variant X-47574355-A-G is Benign according to our data. Variant chrX-47574355-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 465091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1629T>C	p.Pro543Pro	synonymous_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1629T>C	p.Pro543Pro	synonymous_variant	Exon 12 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1629T>C	p.Pro543Pro	synonymous_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1629T>C	p.Pro543Pro	synonymous_variant	Exon 12 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.70+333T>C		intron_variant	Intron 1 of 1	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 917869 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 285603

African (AFR) AF: 0.00 AC: 0 AN: 19294

American (AMR) AF: 0.00 AC: 0 AN: 10820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12863

East Asian (EAS) AF: 0.00 AC: 0 AN: 21144

South Asian (SAS) AF: 0.0000322 AC: 1 AN: 31034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2438

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 759518

Other (OTH) AF: 0.00 AC: 0 AN: 38452

GnomAD4 genome Cov.: 23

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 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.8
PromoterAI		0.0096	Neutral

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: rs1027134708; hg19: chrX-47433754;