rs61421477

chr6-33443522-C-T

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.2970C>T(p.Ser990=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,614,142 control chromosomes in the GnomAD database, including 1,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (541 hom., cov: 32)
  • Exomes 𝑓: 0.016 (625 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.340

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=-0.71).
• BP6: Variant 6-33443522-C-T is Benign according to our data. Variant chr6-33443522-C-T is described in ClinVar as [Benign]. Clinvar id is 130529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33443522-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.2970C>T	p.Ser990=	synonymous_variant	15/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.329+3084G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2970C>T	p.Ser990=	synonymous_variant	15/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.377+3084G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8253 AN: 152156 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00751

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0593

GnomAD3 exomes AF: 0.0239 AC: 5998 AN: 251362 Hom.: 260 AF XY: 0.0211 AC XY: 2872 AN XY: 135894

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00527

Gnomad SAS exome AF: 0.0164

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0159 AC: 23227 AN: 1461868 Hom.: 625 Cov.: 33 AF XY: 0.0155 AC XY: 11296 AN XY: 727232

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.00310

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.00258

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0543 AC: 8275 AN: 152274 Hom.: 541 Cov.: 32 AF XY: 0.0519 AC XY: 3861 AN XY: 74452

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.00714

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0360 Hom.: 164

Bravo AF: 0.0630

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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

Mar 18, 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.1
Dann	Benign	0.59
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: rs61421477; hg19: chr6-33411299; COSMIC: COSV53385570; COSMIC: COSV53385570;