rs62636605

Variant names:

• chrX-47576566-G-A
• rs62636605
• NM_006950.3:c.912C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006950.3(SYN1):​c.912C>T​(p.Ala304Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,210,006 control chromosomes in the GnomAD database, including 60 homozygotes. There are 838 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., 393 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (37 hom. 445 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.82

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-47576566-G-A is Benign according to our data. Variant chrX-47576566-G-A is described in ClinVar as [Benign]. Clinvar id is 130386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (1487/111775) while in subpopulation AFR AF= 0.0458 (1406/30684). AF 95% confidence interval is 0.0438. There are 23 homozygotes in gnomad4. There are 393 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.912C>T	p.Ala304Ala	synonymous_variant	Exon 7 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.912C>T	p.Ala304Ala	synonymous_variant	Exon 7 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.912C>T	p.Ala304Ala	synonymous_variant	Exon 7 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.912C>T	p.Ala304Ala	synonymous_variant	Exon 7 of 13	1		ENSP00000343206.4
ENSG00000283743	ENST00000638776.2	n.3368C>T		non_coding_transcript_exon_variant	Exon 13 of 16	5

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 1479 AN: 111720 Hom.: 23 Cov.: 23 AF XY: 0.0114 AC XY: 386 AN XY: 33884

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000742

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.00386 AC: 709 AN: 183492 Hom.: 13 AF XY: 0.00244 AC XY: 166 AN XY: 67920

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00151 AC: 1659 AN: 1098231 Hom.: 37 Cov.: 33 AF XY: 0.00122 AC XY: 445 AN XY: 363585

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.00352

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000388

Gnomad4 FIN exome AF: 0.0000493

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.0133 AC: 1487 AN: 111775 Hom.: 23 Cov.: 23 AF XY: 0.0116 AC XY: 393 AN XY: 33949

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.00548

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000372

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.00617 Hom.: 22

Bravo AF: 0.0160

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 06, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

History of neurodevelopmental disorder Benign:1

Apr 13, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.41
DANN	Benign	0.88

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: rs62636605; hg19: chrX-47435965;