rs754389007
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006772.3(SYNGAP1):c.1677-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,567,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
SYNGAP1
NM_006772.3 splice_polypyrimidine_tract, intron
NM_006772.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.0007383
2
Clinical Significance
Conservation
PhyloP100: 0.398
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
Variant 6-33440720-T-C is Benign according to our data. Variant chr6-33440720-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 537018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000224 (34/151918) while in subpopulation AFR AF= 0.00075 (31/41352). AF 95% confidence interval is 0.000543. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 34 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNGAP1 | NM_006772.3 | c.1677-9T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000646630.1 | |||
SYNGAP1-AS1 | NR_174954.1 | n.330-3239A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNGAP1 | ENST00000646630.1 | c.1677-9T>C | splice_polypyrimidine_tract_variant, intron_variant | NM_006772.3 | P1 | ||||
SYNGAP1-AS1 | ENST00000630418.1 | n.378-3239A>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000224 AC: 34AN: 151918Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000441 AC: 8AN: 181332Hom.: 0 AF XY: 0.0000414 AC XY: 4AN XY: 96664
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GnomAD4 exome AF: 0.0000205 AC: 29AN: 1415844Hom.: 0 Cov.: 33 AF XY: 0.0000186 AC XY: 13AN XY: 700526
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GnomAD4 genome ? AF: 0.000224 AC: 34AN: 151918Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74194
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2019 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at