rs781201249

Variant names:

• chr6-33443750-T-G
• rs781201249
• NM_006772.3:c.3198T>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006772.3(SYNGAP1):​c.3198T>G​(p.Pro1066Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,607,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0890
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-33443750-T-G is Benign according to our data. Variant chr6-33443750-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 416788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.089 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 25 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.3198T>G	p.Pro1066Pro	synonymous	Exon 15 of 19	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.3156T>G	p.Pro1052Pro	synonymous	Exon 14 of 18	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.329+2856A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3198T>G	p.Pro1066Pro	synonymous	Exon 15 of 19	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.3198T>G	p.Pro1066Pro	synonymous	Exon 15 of 19	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.3156T>G	p.Pro1052Pro	synonymous	Exon 14 of 18	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151520 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000207 AC: 5 AN: 241552 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1455958 Hom.: 0 Cov.: 65 AF XY: 0.0000180 AC XY: 13 AN XY: 723386

African (AFR) AF: 0.000120 AC: 4 AN: 33380

American (AMR) AF: 0.0000449 AC: 2 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51902

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5750

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108566

Other (OTH) AF: 0.0000332 AC: 2 AN: 60176

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73966

African (AFR) AF: 0.00 AC: 0 AN: 41172

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67848

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal dominant 5 (1)
-	-	1	not provided (1)
-	-	1	SYNGAP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.6
DANN	Benign	0.57
PhyloP100		-0.089
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781201249; hg19: chr6-33411527;