6-33451852-A-G

Variant names:

• chr6-33451852-A-G
• rs745764103
• NM_006772.3:c.3978A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006772.3(SYNGAP1):​c.3978A>G​(p.Pro1326Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 359,392 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. Synonymous variant affecting the same amino acid position (i.e. P1326P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3978A>G	p.Pro1326Pro	synonymous_variant	Exon 19 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3978A>G	p.Pro1326Pro	synonymous_variant	Exon 19 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.*50A>G		3_prime_UTR_variant	Exon 19 of 19			ENSP00000495541.1
SYNGAP1	ENST00000418600.7	c.*132A>G		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.*50A>G		3_prime_UTR_variant	Exon 17 of 17			ENSP00000494861.1
SYNGAP1	ENST00000449372.7	c.*50A>G		downstream_gene_variant		5		ENSP00000416519.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000278 AC: 1 AN: 359392 Hom.: 0 Cov.: 23 AF XY: 0.00000560 AC XY: 1 AN XY: 178540

⚠️ 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: 7538

American (AMR) AF: 0.00 AC: 0 AN: 7826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6940

East Asian (EAS) AF: 0.00 AC: 0 AN: 8754

South Asian (SAS) AF: 0.0000422 AC: 1 AN: 23724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1338

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 276306

Other (OTH) AF: 0.00 AC: 0 AN: 14606

⚠️ 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.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.2
DANN	Benign	0.74
PhyloP100		2.1

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: rs745764103; hg19: chr6-33419629;