rs150153477

chr6-33440828-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006772.3(SYNGAP1):c.1776A>G(p.Ser592=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,806 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.41

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=-0.82).
• BP6: Variant 6-33440828-A-G is Benign according to our data. Variant chr6-33440828-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 240705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33440828-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000961 (146/151926) while in subpopulation SAS AF= 0.00457 (22/4814). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.1776A>G	p.Ser592=	synonymous_variant	11/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.330-3347T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1776A>G	p.Ser592=	synonymous_variant	11/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.378-3347T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000962 AC: 146 AN: 151808 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00160 AC: 402 AN: 251420 Hom.: 1 AF XY: 0.00191 AC XY: 259 AN XY: 135880

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00529

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00111 AC: 1629 AN: 1461880 Hom.: 8 Cov.: 38 AF XY: 0.00125 AC XY: 911 AN XY: 727238

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00495

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000790

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.000961 AC: 146 AN: 151926 Hom.: 0 Cov.: 31 AF XY: 0.000915 AC XY: 68 AN XY: 74280

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00457

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00138 Hom.: 3

Bravo AF: 0.000948

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 30, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNGAP1: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2016

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. -

Intellectual disability, autosomal dominant 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

SYNGAP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.1
Dann	Benign	0.62
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: rs150153477; hg19: chr6-33408605;