chr6-33438779-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: 0.214

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

Verdict is Benign. Variant got -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 id is 130523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33438779-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.1536A>G	p.Glu512Glu	synonymous_variant	Exon 10 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1536A>G	p.Glu512Glu	synonymous_variant	Exon 10 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.1536A>G	p.Glu512Glu	synonymous_variant	Exon 10 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.1536A>G	p.Glu512Glu	synonymous_variant	Exon 10 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.1536A>G	p.Glu512Glu	synonymous_variant	Exon 10 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1359A>G	p.Glu453Glu	synonymous_variant	Exon 8 of 17			ENSP00000494861.1

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

GnomAD3 exomes AF: 0.0347 AC: 8731 AN: 251478 Hom.: 404 AF XY: 0.0323 AC XY: 4393 AN XY: 135920

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 SAS exome AF: 0.0309

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

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.0447

Gnomad4 EAS exome AF: 0.00982

Gnomad4 SAS exome AF: 0.0307

Gnomad4 FIN exome AF: 0.00492

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.0360

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

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0445

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.0237

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0690

Alfa AF: 0.0438 Hom.: 265

Bravo AF: 0.0796

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.0270

EpiControl AF: 0.0285

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

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. -

Inborn genetic diseases Benign:1

Mar 18, 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: 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. -

Intellectual disability, autosomal dominant 5 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 17, 2018

GeneDx

Significance: 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	-0.68
CADD	Benign	5.3
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs7759963; hg19: chr6-33406556;