rs10807124

Variant names:

• chr6-33436287-G-A
• rs10807124
• NM_006772.3:c.762+674G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006772.3(SYNGAP1):​c.762+674G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 151,114 control chromosomes in the GnomAD database, including 5,638 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (5638 hom., cov: 31)
• Consequence: SYNGAP1 NM_006772.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.402
• Publications: 15 publications found

Genes affected

SYNGAP1 (HGNC:11497): (synaptic Ras GTPase activating protein 1) This gene encodes a Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex. The N-terminal domain of the protein contains a Ras-GAP domain, a pleckstrin homology domain, and a C2 domain that may be involved in binding of calcium and phospholipids. The C-terminal domain consists of a ten histidine repeat region, serine and tyrosine phosphorylation sites, and a T/SXV motif required for postsynaptic scaffold protein interaction. The encoded protein negatively regulates Ras, Rap and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking to the postsynaptic membrane to regulate synaptic plasticity and neuronal homeostasis. Allelic variants of this gene are associated with intellectual disability and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SYNGAP1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SYNGAP1-related developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006772.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.762+674G>A		intron	N/A	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.762+674G>A		intron	N/A	NP_001123538.1	B7ZCA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.762+674G>A		intron	N/A	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.762+674G>A		intron	N/A	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.762+674G>A		intron	N/A	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36062 AN: 151056 Hom.: 5642 Cov.: 31

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.239 AC: 36053 AN: 151114 Hom.: 5638 Cov.: 31 AF XY: 0.251 AC XY: 18485 AN XY: 73772

African (AFR) AF: 0.0495 AC: 2030 AN: 41000

American (AMR) AF: 0.292 AC: 4438 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3464

East Asian (EAS) AF: 0.278 AC: 1436 AN: 5162

South Asian (SAS) AF: 0.343 AC: 1636 AN: 4764

European-Finnish (FIN) AF: 0.520 AC: 5400 AN: 10388

Middle Eastern (MID) AF: 0.137 AC: 39 AN: 284

European-Non Finnish (NFE) AF: 0.291 AC: 19754 AN: 67838

Other (OTH) AF: 0.193 AC: 404 AN: 2098

Alfa AF: 0.250 Hom.: 5531

Bravo AF: 0.211

Asia WGS AF: 0.241 AC: 837 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.6
DANN	Benign	0.54
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs10807124; hg19: chr6-33404064;