rs749376396
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_006772.3(SYNGAP1):āc.3913A>Gā(p.Thr1305Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 31)
Exomes š: 0.000017 ( 0 hom. )
Consequence
SYNGAP1
NM_006772.3 missense
NM_006772.3 missense
Scores
1
13
Clinical Significance
Conservation
PhyloP100: 3.67
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 -12 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SYNGAP1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.02316174).
BP6
?
Variant 6-33451787-A-G is Benign according to our data. Variant chr6-33451787-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411587.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000329 (5/152004) while in subpopulation AMR AF= 0.000328 (5/15262). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYNGAP1 | NM_006772.3 | c.3913A>G | p.Thr1305Ala | missense_variant | 19/19 | ENST00000646630.1 | |
SYNGAP1-AS1 | NR_174954.1 | n.136+2483T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYNGAP1 | ENST00000646630.1 | c.3913A>G | p.Thr1305Ala | missense_variant | 19/19 | NM_006772.3 | P1 | ||
SYNGAP1-AS1 | ENST00000630418.1 | n.184+2483T>C | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152004Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000723 AC: 18AN: 249008Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135156
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461278Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726898
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152004Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74236
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 5 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 28, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;N;N
PrimateAI
Pathogenic
D
Polyphen
B;B;.
Vest4
0.094, 0.22
MutPred
Loss of glycosylation at T1305 (P = 0.0238);Loss of glycosylation at T1305 (P = 0.0238);.;
MVP
0.043
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at