rs1057519546
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_006772.3(SYNGAP1):c.509G>A(p.Arg170Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006772.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNGAP1 | NM_006772.3 | c.509G>A | p.Arg170Gln | missense_variant, splice_region_variant | 5/19 | ENST00000646630.1 | NP_006763.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNGAP1 | ENST00000646630.1 | c.509G>A | p.Arg170Gln | missense_variant, splice_region_variant | 5/19 | NM_006772.3 | ENSP00000496007.1 | |||
SYNGAP1 | ENST00000644458.1 | c.509G>A | p.Arg170Gln | missense_variant, splice_region_variant | 5/19 | ENSP00000495541.1 | ||||
SYNGAP1 | ENST00000449372.7 | c.509G>A | p.Arg170Gln | missense_variant, splice_region_variant | 5/18 | 5 | ENSP00000416519.4 | |||
SYNGAP1 | ENST00000418600.7 | c.509G>A | p.Arg170Gln | missense_variant, splice_region_variant | 5/19 | 5 | ENSP00000403636.3 | |||
SYNGAP1 | ENST00000645250.1 | c.332G>A | p.Arg111Gln | missense_variant, splice_region_variant | 3/17 | ENSP00000494861.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 38
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 5 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3+PP2+PS4_Moderate+PS2_VeryStrong+PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | May 22, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000375528 / PMID: 26079862). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2024 | RNA studies demonstrate a damaging effect: altered splicing with 34 bp insertion of intron 5 that is out-of-frame (PMID: 38113761); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27864847, 25533962, 28191890, 30541864, 31785789, 36035117, 35982159, 38113761, 33057194, 32427350, 35979408, 38505260, 29381230, 31487502, 33308442, 26079862) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at