6-33440855-G-A

Variant names:

• chr6-33440855-G-A
• rs77934848
• NM_006772.3:c.1803G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006772.3(SYNGAP1):​c.1803G>A​(p.Ala601Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,242 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A601A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (51 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.719
• Publications: 3 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=-0.5).
• BP6: Variant 6-33440855-G-A is Benign according to our data. Variant chr6-33440855-G-A is described in ClinVar as Benign. ClinVar VariationId is 416776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.719 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00189 (288/152348) while in subpopulation EAS AF = 0.0384 (199/5188). AF 95% confidence interval is 0.034. There are 4 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 288 AD,Unknown gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.1803G>A	p.Ala601Ala	synonymous	Exon 11 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.1803G>A	p.Ala601Ala	synonymous	Exon 11 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.330-3374C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.1803G>A	p.Ala601Ala	synonymous	Exon 11 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.1803G>A	p.Ala601Ala	synonymous	Exon 11 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.1803G>A	p.Ala601Ala	synonymous	Exon 11 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152230 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00348 AC: 876 AN: 251486 AF XY: 0.00319

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0399

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00164 AC: 2399 AN: 1461894 Hom.: 51 Cov.: 39 AF XY: 0.00157 AC XY: 1143 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0453 AC: 1797 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86258

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1112012

Other (OTH) AF: 0.00301 AC: 182 AN: 60396

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152348 Hom.: 4 Cov.: 31 AF XY: 0.00193 AC XY: 144 AN XY: 74502

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0384 AC: 199 AN: 5188

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4828

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.00161

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 18, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Mar 24, 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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNGAP1-related disorder Benign:1

Sep 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Apr 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77934848; hg19: chr6-33408632; COSMIC: COSV53384532; COSMIC: COSV53384532;