rs7759963

Variant names:

• chr6-33438779-A-G
• rs7759963
• NM_006772.3:c.1536A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006772.3(SYNGAP1):​c.1536A>G​(p.Glu512Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,613,972 control chromosomes in the GnomAD database, including 1,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (802 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1081 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.214
• Publications: 5 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-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 6-33438779-A-G is Benign according to our data. Variant chr6-33438779-A-G is described in ClinVar as Benign. ClinVar VariationId is 130523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.214 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 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.1536A>G	p.Glu512Glu	synonymous	Exon 10 of 19	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.1536A>G	p.Glu512Glu	synonymous	Exon 10 of 18	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.330-1298T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.1536A>G	p.Glu512Glu	synonymous	Exon 10 of 19	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.1536A>G	p.Glu512Glu	synonymous	Exon 10 of 19	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.1536A>G	p.Glu512Glu	synonymous	Exon 10 of 18	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes AF: 0.0688 AC: 10460 AN: 151976 Hom.: 798 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0445

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0697

GnomAD2 exomes AF: 0.0347 AC: 8731 AN: 251478 AF XY: 0.0323

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.0165

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0378

GnomAD4 exome AF: 0.0240 AC: 35075 AN: 1461878 Hom.: 1081 Cov.: 34 AF XY: 0.0238 AC XY: 17343 AN XY: 727240

African (AFR) AF: 0.192 AC: 6413 AN: 33478

American (AMR) AF: 0.0352 AC: 1574 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 1169 AN: 26136

East Asian (EAS) AF: 0.00982 AC: 390 AN: 39700

South Asian (SAS) AF: 0.0307 AC: 2647 AN: 86258

European-Finnish (FIN) AF: 0.00492 AC: 263 AN: 53420

Middle Eastern (MID) AF: 0.0908 AC: 524 AN: 5768

European-Non Finnish (NFE) AF: 0.0179 AC: 19920 AN: 1111998

Other (OTH) AF: 0.0360 AC: 2175 AN: 60396

GnomAD4 genome AF: 0.0689 AC: 10482 AN: 152094 Hom.: 802 Cov.: 32 AF XY: 0.0671 AC XY: 4988 AN XY: 74378

African (AFR) AF: 0.187 AC: 7762 AN: 41434

American (AMR) AF: 0.0445 AC: 680 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3468

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5182

South Asian (SAS) AF: 0.0237 AC: 114 AN: 4814

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10604

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0211 AC: 1437 AN: 67974

Other (OTH) AF: 0.0690 AC: 146 AN: 2116

Alfa AF: 0.0450 Hom.: 303

Bravo AF: 0.0796

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.0270

EpiControl AF: 0.0285

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.3
DANN	Benign	0.69
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7759963; hg19: chr6-33406556;