NM_006772.3:c.67+15delG

Variant names:

• chr6-33420340-TG-T
• rs753367470
• NM_006772.3:c.67+15delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006772.3(SYNGAP1):​c.67+15delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,171,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.13
• 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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SYNGAP1-related developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-33420340-TG-T is Benign according to our data. Variant chr6-33420340-TG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 537014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000648 (8/123542) while in subpopulation EAS AF = 0.00198 (8/4040). AF 95% confidence interval is 0.000985. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.67+15delG		intron	N/A	NP_006763.2
	SYNGAP1	NM_001130066.2		c.67+15delG		intron	N/A	NP_001123538.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.67+10delG		intron	N/A	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.67+10delG		intron	N/A	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.67+10delG		intron	N/A	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.0000648 AC: 8 AN: 123428 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000162 AC: 18 AN: 111354 AF XY: 0.000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000372 AC: 39 AN: 1047766 Hom.: 0 Cov.: 26 AF XY: 0.0000401 AC XY: 21 AN XY: 523186

African (AFR) AF: 0.00 AC: 0 AN: 24362

American (AMR) AF: 0.00 AC: 0 AN: 31710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19996

East Asian (EAS) AF: 0.000854 AC: 23 AN: 26936

South Asian (SAS) AF: 0.0000150 AC: 1 AN: 66584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3048

European-Non Finnish (NFE) AF: 0.0000126 AC: 10 AN: 794202

Other (OTH) AF: 0.000115 AC: 5 AN: 43412

GnomAD4 genome AF: 0.0000648 AC: 8 AN: 123542 Hom.: 0 Cov.: 28 AF XY: 0.0000667 AC XY: 4 AN XY: 59928

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 13138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2964

East Asian (EAS) AF: 0.00198 AC: 8 AN: 4040

South Asian (SAS) AF: 0.00 AC: 0 AN: 2982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56232

Other (OTH) AF: 0.00 AC: 0 AN: 1732

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Intellectual disability, autosomal dominant 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

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: rs753367470; hg19: chr6-33388117;