chr6-33440765-G-A

Variant names:

• chr6-33440765-G-A
• rs411136
• NM_006772.3:c.1713G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006772.3(SYNGAP1):​c.1713G>A​(p.Ser571Ser) 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:5
• Conservation: PhyloP100: -4.11
• Publications: 33 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=-0.85).
• BP6: Variant 6-33440765-G-A is Benign according to our data. Variant chr6-33440765-G-A is described in ClinVar as Benign. ClinVar VariationId is 130524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1713G>A	p.Ser571Ser	synonymous	Exon 11 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.1713G>A	p.Ser571Ser	synonymous	Exon 11 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.330-3284C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.1713G>A	p.Ser571Ser	synonymous	Exon 11 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.1713G>A	p.Ser571Ser	synonymous	Exon 11 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.1713G>A	p.Ser571Ser	synonymous	Exon 11 of 18	ENSP00000416519.4

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

GnomAD2 exomes AF: 0.402 AC: 95212 AN: 236684 AF XY: 0.408

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 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

African (AFR) AF: 0.271 AC: 9007 AN: 33258

American (AMR) AF: 0.367 AC: 15935 AN: 43394

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11335 AN: 25998

East Asian (EAS) AF: 0.638 AC: 25095 AN: 39330

South Asian (SAS) AF: 0.499 AC: 42595 AN: 85442

European-Finnish (FIN) AF: 0.278 AC: 14601 AN: 52518

Middle Eastern (MID) AF: 0.470 AC: 2706 AN: 5760

European-Non Finnish (NFE) AF: 0.404 AC: 448141 AN: 1108338

Other (OTH) AF: 0.408 AC: 24492 AN: 60054

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

African (AFR) AF: 0.278 AC: 11524 AN: 41436

American (AMR) AF: 0.385 AC: 5884 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1472 AN: 3466

East Asian (EAS) AF: 0.607 AC: 3138 AN: 5168

South Asian (SAS) AF: 0.506 AC: 2437 AN: 4818

European-Finnish (FIN) AF: 0.255 AC: 2695 AN: 10578

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26818 AN: 67964

Other (OTH) AF: 0.397 AC: 839 AN: 2112

Alfa AF: 0.384 Hom.: 31012

Bravo AF: 0.366

Asia WGS AF: 0.566 AC: 1966 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.93
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs411136; hg19: chr6-33408542; COSMIC: COSV53379358; COSMIC: COSV53379358;