6-33437403-G-A

Position:

• chr6-33437403-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006772.3(SYNGAP1):​c.763-265G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 567,158 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.055 (559 hom., cov: 31)
  • Exomes 𝑓: 0.018 (241 hom.)
• Consequence: SYNGAP1 NM_006772.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.55

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:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 6-33437403-G-A is Benign according to our data. Variant chr6-33437403-G-A is described in ClinVar as [Benign]. Clinvar id is 1250851.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.763-265G>A		intron_variant		ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.763-265G>A		intron_variant			NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.763-265G>A		intron_variant				ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.763-265G>A		intron_variant		5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.763-265G>A		intron_variant		5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.586-265G>A		intron_variant				ENSP00000494861.1

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8366 AN: 151940 Hom.: 555 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0184 AC: 7635 AN: 415100 Hom.: 241 Cov.: 4 AF XY: 0.0176 AC XY: 3824 AN XY: 217310

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0303

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.00260

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.00291

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0552 AC: 8387 AN: 152058 Hom.: 559 Cov.: 31 AF XY: 0.0527 AC XY: 3921 AN XY: 74358

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0324

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.00734

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.0586

Alfa AF: 0.0395 Hom.: 38

Bravo AF: 0.0643

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-1.0
CADD	Benign	2.1
DANN	Benign	0.51

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: rs60719642; hg19: chr6-33405180;