rs869312674
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_006772.3(SYNGAP1):c.3583-6G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006772.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNGAP1 | NM_006772.3 | c.3583-6G>A | splice_region_variant, intron_variant | Intron 16 of 18 | ENST00000646630.1 | NP_006763.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNGAP1 | ENST00000646630.1 | c.3583-6G>A | splice_region_variant, intron_variant | Intron 16 of 18 | NM_006772.3 | ENSP00000496007.1 | ||||
SYNGAP1 | ENST00000644458.1 | c.3583-6G>A | splice_region_variant, intron_variant | Intron 16 of 18 | ENSP00000495541.1 | |||||
SYNGAP1 | ENST00000449372.7 | c.3541-12G>A | intron_variant | Intron 15 of 17 | 5 | ENSP00000416519.4 | ||||
SYNGAP1 | ENST00000418600.7 | c.3583-6G>A | splice_region_variant, intron_variant | Intron 16 of 18 | 5 | ENSP00000403636.3 | ||||
SYNGAP1 | ENST00000645250.1 | c.3406-6G>A | splice_region_variant, intron_variant | Intron 14 of 16 | ENSP00000494861.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461346Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726958
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 5 Pathogenic:5
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This sequence change falls in intron 16 of the SYNGAP1 gene. It does not directly change the encoded amino acid sequence of the SYNGAP1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with SYNGAP1-related conditions (PMID: 25167861, 28554332). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224094). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder 5 (MIM#612621). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). mRNA analysis from an affected individual describes this variant as resulting in the formation of a cryptic acceptor site, and a frameshift outcome (p.Val1195Alafs*27)). However, no mRNA data or results were shown (PMID: 25167861). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing in silico tools were inconclusive and affected nucleotide is highly conserved. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS (PMID: 28554332), but moreso as likely pathogenic and pathogenic, and observed de novo in several individuals with features including global developmental delay, intellectual disability and hypotonia (PMID: 25167861, PMID: 30800045, PMID: 33639450). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Criteria applied: PS2,PS4_MOD,PM2_SUP -
SYNGAP1-related disorder Pathogenic:1
The SYNGAP1 c.3583-6G>A variant is predicted to interfere with splicing. This variant has been reported in the heterozygous, de novo state in an individual with intellectual disability (APN-139; Figure S8 and Table S9, Redin et al. 2014. PubMed ID: 25167861), an individual with intellectual disability (moderate), autism spectrum disorder, speech delay and seizures (Table S2, Bowling et al. 2017. PubMed ID: 28554332), and in an individual with autism, severe cognitive disability, nystagmus, feeding issues, aspecific white matter hypersignal, seizures, and no speech (Patient ID 8, Lo Barco et al. 2021. PubMed ID: 33639450). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28524815, 28721930, 25167861, 28554332, 33639450, 34070602) -
Intellectual disability Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at