6-33432683-A-G

Variant names:

• chr6-33432683-A-G
• rs797045012
• NM_006772.3:c.388-2A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006772.3(SYNGAP1):​c.388-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 9)
• Consequence: SYNGAP1 NM_006772.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-33432683-A-G is Pathogenic according to our data. Variant chr6-33432683-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208499.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.388-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 18	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.388-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 18		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.388-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 18			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.388-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 17	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.388-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 18	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.211-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 16			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1

Jun 09, 2014

Mendelics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Benign	0.96
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.86	D
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045012; hg19: chr6-33400460;