NM_006950.3:c.1968G>A

Variant names:

• chrX-47574016-C-T
• rs199844514
• NM_006950.3:c.1968G>A

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.1968G>A​(p.Pro656Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,144,087 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00011 (0 hom. 30 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.95

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-47574016-C-T is Benign according to our data. Variant chrX-47574016-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 207464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000196 (22/112524) while in subpopulation EAS AF= 0.00457 (16/3502). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1968G>A	p.Pro656Pro	synonymous_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1968G>A	p.Pro656Pro	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.1968G>A	p.Pro656Pro	synonymous_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1968G>A	p.Pro656Pro	synonymous_variant	Exon 12 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.70+672G>A		intron_variant	Intron 1 of 1	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112474 Hom.: 0 Cov.: 24 AF XY: 0.000173 AC XY: 6 AN XY: 34656

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00455

Gnomad SAS AF: 0.000359

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.000659

GnomAD3 exomes AF: 0.000229 AC: 19 AN: 83074 Hom.: 0 AF XY: 0.000258 AC XY: 5 AN XY: 19376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00255

Gnomad SAS exome AF: 0.0000892

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000812

GnomAD4 exome AF: 0.000107 AC: 110 AN: 1031563 Hom.: 0 Cov.: 32 AF XY: 0.0000905 AC XY: 30 AN XY: 331343

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00214

Gnomad4 SAS exome AF: 0.000228

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000123

Gnomad4 OTH exome AF: 0.000939

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112524 Hom.: 0 Cov.: 24 AF XY: 0.000173 AC XY: 6 AN XY: 34716

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000185

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00457

Gnomad4 SAS AF: 0.000360

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.000651

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 31, 2014

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. -

Inborn genetic diseases Benign:1

Apr 13, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -

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

Sep 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	-0.51
CADD	Benign	6.3
DANN	Benign	0.90

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: rs199844514; hg19: chrX-47433415; COSMIC: COSV99927246; COSMIC: COSV99927246;