rs1554122884

Variant names:

• chr6-33447854-T-A
• rs1554122884
• NM_006772.3:c.3806T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006772.3(SYNGAP1):​c.3806T>A​(p.Val1269Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3806T>A	p.Val1269Glu	missense_variant	Exon 18 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3806T>A	p.Val1269Glu	missense_variant	Exon 18 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.3806T>A	p.Val1269Glu	missense_variant	Exon 18 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.3758T>A	p.Val1253Glu	missense_variant	Exon 17 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000645250.1	c.3629T>A	p.Val1210Glu	missense_variant	Exon 16 of 17			ENSP00000494861.1
SYNGAP1	ENST00000418600.7	c.3819T>A	p.Gly1273Gly	synonymous_variant	Exon 18 of 19	5		ENSP00000403636.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 19, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.3806T>A (p.V1269E) alteration is located in coding exon 18 of the SYNGAP1 gene. This alteration results from a T to A substitution at nucleotide position 3806, causing the valine (V) at amino acid position 1269 to be replaced by a glutamic acid (E). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the SYNGAP1 c.3806T>A alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V1269 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.V1269E alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.9	.;.;.;D;.;D;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	.;.;.;D;.;D;.
Sift4G	Uncertain	0.023	.;D;.;D;D;D;.
Polyphen		1.0	D;D;.;.;D;.;.
Vest4		0.69, 0.68, 0.67
MutPred		0.22		Loss of MoRF binding (P = 0.043);Loss of MoRF binding (P = 0.043);Loss of MoRF binding (P = 0.043);.;Loss of MoRF binding (P = 0.043);.;.;
MVP		0.64
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.93

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: rs1554122884; hg19: chr6-33415631;