NM_006772.3:c.3363C>T

Variant names:

• chr6-33443915-C-T
• rs1478769596
• NM_006772.3:c.3363C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_006772.3(SYNGAP1):​c.3363C>T​(p.Ser1121Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 921,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.887
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 6-33443915-C-T is Benign according to our data. Variant chr6-33443915-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436919.
• BP7: Synonymous conserved (PhyloP=0.887 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.3363C>T	p.Ser1121Ser	synonymous	Exon 15 of 19	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.3321C>T	p.Ser1107Ser	synonymous	Exon 14 of 18	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.329+2691G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3363C>T	p.Ser1121Ser	synonymous	Exon 15 of 19	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.3363C>T	p.Ser1121Ser	synonymous	Exon 15 of 19	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.3321C>T	p.Ser1107Ser	synonymous	Exon 14 of 18	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000670 AC: 1 AN: 149344 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000527

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 17 AN: 921188 Hom.: 0 Cov.: 44 AF XY: 0.0000266 AC XY: 12 AN XY: 451930

African (AFR) AF: 0.00 AC: 0 AN: 20024

American (AMR) AF: 0.0000476 AC: 1 AN: 21020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10206

East Asian (EAS) AF: 0.00 AC: 0 AN: 18700

South Asian (SAS) AF: 0.00 AC: 0 AN: 58478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28826

Middle Eastern (MID) AF: 0.000296 AC: 1 AN: 3376

European-Non Finnish (NFE) AF: 0.0000179 AC: 13 AN: 726408

Other (OTH) AF: 0.0000586 AC: 2 AN: 34150

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal dominant 5 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.8
DANN	Benign	0.63
PhyloP100		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1478769596; hg19: chr6-33411692; COSMIC: COSV99538430; COSMIC: COSV99538430;