NM_006772.3:c.763-265G>A

Variant names:

• chr6-33437403-G-A
• rs60719642
• NM_006772.3:c.763-265G>A

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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.

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.763-265G>A		intron	N/A	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.763-265G>A		intron	N/A	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.408C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.763-265G>A		intron	N/A	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.763-265G>A		intron	N/A	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.763-265G>A		intron	N/A	ENSP00000416519.4	B7ZCA0

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

African (AFR) AF: 0.159 AC: 1878 AN: 11838

American (AMR) AF: 0.0303 AC: 504 AN: 16630

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 331 AN: 12806

East Asian (EAS) AF: 0.00260 AC: 72 AN: 27660

South Asian (SAS) AF: 0.0159 AC: 648 AN: 40648

European-Finnish (FIN) AF: 0.00291 AC: 77 AN: 26446

Middle Eastern (MID) AF: 0.0529 AC: 96 AN: 1816

European-Non Finnish (NFE) AF: 0.0132 AC: 3334 AN: 253252

Other (OTH) AF: 0.0290 AC: 695 AN: 24004

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

African (AFR) AF: 0.160 AC: 6610 AN: 41438

American (AMR) AF: 0.0324 AC: 495 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 98 AN: 3464

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5176

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4806

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10592

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 894 AN: 67990

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0442 Hom.: 51

Bravo AF: 0.0643

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.1
DANN	Benign	0.51
PhyloP100		-1.6
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: rs60719642; hg19: chr6-33405180;