6-33437546-C-T

Variant names:

• chr6-33437546-C-T
• rs144595467
• NM_006772.3:c.763-122C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006772.3(SYNGAP1):​c.763-122C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,374,872 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (6 hom.)
• Consequence: SYNGAP1 NM_006772.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00400
• 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=-0.86).
• BP6: Variant 6-33437546-C-T is Benign according to our data. Variant chr6-33437546-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1212652.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00569 (867/152282) while in subpopulation AFR AF = 0.0194 (805/41546). AF 95% confidence interval is 0.0183. There are 9 homozygotes in GnomAd4. There are 417 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 867 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.763-122C>T		intron	N/A	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.763-122C>T		intron	N/A	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.330-65G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.763-122C>T		intron	N/A	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.763-122C>T		intron	N/A	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000449372.7	TSL:5	c.763-122C>T		intron	N/A	ENSP00000416519.4	B7ZCA0

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 865 AN: 152164 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.000575 AC: 703 AN: 1222590 Hom.: 6 Cov.: 18 AF XY: 0.000488 AC XY: 299 AN XY: 613130

African (AFR) AF: 0.0170 AC: 491 AN: 28818

American (AMR) AF: 0.00180 AC: 77 AN: 42702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22946

East Asian (EAS) AF: 0.00 AC: 0 AN: 38294

South Asian (SAS) AF: 0.0000644 AC: 5 AN: 77588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42620

Middle Eastern (MID) AF: 0.000795 AC: 3 AN: 3772

European-Non Finnish (NFE) AF: 0.0000547 AC: 50 AN: 913558

Other (OTH) AF: 0.00147 AC: 77 AN: 52292

GnomAD4 genome AF: 0.00569 AC: 867 AN: 152282 Hom.: 9 Cov.: 32 AF XY: 0.00560 AC XY: 417 AN XY: 74472

African (AFR) AF: 0.0194 AC: 805 AN: 41546

American (AMR) AF: 0.00288 AC: 44 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00458 Hom.: 0

Bravo AF: 0.00637

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.86
CADD	Benign	5.7
DANN	Benign	0.68
PhyloP100		-0.0040
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: rs144595467; hg19: chr6-33405323;