chr6-33443921-C-T

Variant names:

• chr6-33443921-C-T
• rs779377737
• NM_006772.3:c.3369C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006772.3(SYNGAP1):​c.3369C>T​(p.Gly1123Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 959,724 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.545
• Publications: 1 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-33443921-C-T is Benign according to our data. Variant chr6-33443921-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 537015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.545 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 28 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.3369C>T	p.Gly1123Gly	synonymous	Exon 15 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.3327C>T	p.Gly1109Gly	synonymous	Exon 14 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.329+2685G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3369C>T	p.Gly1123Gly	synonymous	Exon 15 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.3369C>T	p.Gly1123Gly	synonymous	Exon 15 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.3327C>T	p.Gly1109Gly	synonymous	Exon 14 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.00000715 AC: 1 AN: 139958 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000217 AC: 3 AN: 138540 AF XY: 0.0000268

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000772

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000311

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 28 AN: 819766 Hom.: 0 Cov.: 37 AF XY: 0.0000298 AC XY: 12 AN XY: 403316

African (AFR) AF: 0.0000544 AC: 1 AN: 18370

American (AMR) AF: 0.00 AC: 0 AN: 19542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9428

East Asian (EAS) AF: 0.0000555 AC: 1 AN: 18016

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2982

European-Non Finnish (NFE) AF: 0.0000391 AC: 25 AN: 640138

Other (OTH) AF: 0.00 AC: 0 AN: 30446

GnomAD4 genome AF: 0.00000715 AC: 1 AN: 139958 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68238

African (AFR) AF: 0.00 AC: 0 AN: 38198

American (AMR) AF: 0.00 AC: 0 AN: 14174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3334

East Asian (EAS) AF: 0.00 AC: 0 AN: 4246

South Asian (SAS) AF: 0.00 AC: 0 AN: 3804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 64216

Other (OTH) AF: 0.00 AC: 0 AN: 1964

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:1

Aug 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs779377737; hg19: chr6-33411698; COSMIC: COSV53378233; COSMIC: COSV53378233;