chr6-33444624-T-G

Variant names:

• chr6-33444624-T-G
• rs370618729
• NM_006772.3:c.3582+7T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006772.3(SYNGAP1):​c.3582+7T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,456,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001950
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.40
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-33444624-T-G is Benign according to our data. Variant chr6-33444624-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 537016.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 15 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.3582+7T>G		splice_region intron	N/A	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.3540+7T>G		splice_region intron	N/A	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.329+1982A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3582+7T>G		splice_region intron	N/A	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.3582+7T>G		splice_region intron	N/A	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.3540+7T>G		splice_region intron	N/A	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000377 AC: 9 AN: 238908 AF XY: 0.0000310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1456306 Hom.: 0 Cov.: 32 AF XY: 0.00000829 AC XY: 6 AN XY: 723950

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.000182 AC: 8 AN: 43936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 85334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109508

Other (OTH) AF: 0.0000498 AC: 3 AN: 60220

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal dominant 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.11
DANN	Benign	0.57
PhyloP100		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs370618729; hg19: chr6-33412401;