chr6-33451843-A-G

Variant names:

• chr6-33451843-A-G
• rs764031180
• NM_006772.3:c.3969A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The ENST00000646630.1(SYNGAP1):​c.3969A>G​(p.Pro1323Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000498 in 421,808 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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. P1323P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SYNGAP1 ENST00000646630.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.396
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP7: Synonymous conserved (PhyloP=0.396 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000646630.1. 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.3969A>G	p.Pro1323Pro	synonymous	Exon 19 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.*41A>G		3_prime_UTR	Exon 18 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.136+2427T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3969A>G	p.Pro1323Pro	synonymous	Exon 19 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.*41A>G		3_prime_UTR	Exon 19 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000418600.7	TSL:5	c.*123A>G		3_prime_UTR	Exon 19 of 19	ENSP00000403636.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000498 AC: 21 AN: 421808 Hom.: 0 Cov.: 21 AF XY: 0.0000436 AC XY: 9 AN XY: 206204

⚠️ 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: 8960

American (AMR) AF: 0.00 AC: 0 AN: 8432

Ashkenazi Jewish (ASJ) AF: 0.000135 AC: 1 AN: 7432

East Asian (EAS) AF: 0.000203 AC: 2 AN: 9832

South Asian (SAS) AF: 0.00 AC: 0 AN: 25162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1416

European-Non Finnish (NFE) AF: 0.0000484 AC: 16 AN: 330362

Other (OTH) AF: 0.000119 AC: 2 AN: 16860

⚠️ 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.9
DANN	Benign	0.55
PhyloP100		0.40

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: rs764031180; hg19: chr6-33419620;