rs411136

chr6-33440765-G-Achr6-33440765-G-C

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.1713G>A(p.Ser571=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,606,116 control chromosomes in the GnomAD database, including 134,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10569 hom., cov: 31)
  • Exomes 𝑓: 0.41 (124093 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.11

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=-0.85).
• BP6: Variant 6-33440765-G-A is Benign according to our data. Variant chr6-33440765-G-A is described in ClinVar as [Benign]. Clinvar id is 130524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33440765-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.1713G>A	p.Ser571=	synonymous_variant	11/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.330-3284C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1713G>A	p.Ser571=	synonymous_variant	11/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.378-3284C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55343 AN: 151906 Hom.: 10559 Cov.: 31

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.402 AC: 95212 AN: 236684 Hom.: 19841 AF XY: 0.408 AC XY: 52317 AN XY: 128360

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.609

Gnomad SAS exome AF: 0.501

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.392

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.408 AC: 593907 AN: 1454092 Hom.: 124093 Cov.: 74 AF XY: 0.411 AC XY: 297327 AN XY: 722766

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.436

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.364 AC: 55368 AN: 152024 Hom.: 10569 Cov.: 31 AF XY: 0.361 AC XY: 26862 AN XY: 74336

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.397

Alfa AF: 0.381 Hom.: 12038

Bravo AF: 0.366

Asia WGS AF: 0.566 AC: 1966 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.7
Dann	Benign	0.93
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: rs411136; hg19: chr6-33408542; COSMIC: COSV53379358; COSMIC: COSV53379358;