6-33437546-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006772.3(SYNGAP1):​c.763-122C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000818 in 1,222,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

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>A		intron	N/A	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.763-122C>A		intron	N/A	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.330-65G>T		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.18e-7 AC: 1 AN: 1222590 Hom.: 0 Cov.: 18 AF XY: 0.00000163 AC XY: 1 AN XY: 613130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28822

American (AMR) AF: 0.00 AC: 0 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: 0.0000129 AC: 1 AN: 77588

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3772

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 913554

Other (OTH) AF: 0.00 AC: 0 AN: 52292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.2
DANN	Benign	0.74
PhyloP100		-0.0040

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;