6-33438497-C-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_006772.3(SYNGAP1):c.1465C>T(p.Leu489Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SYNGAP1
NM_006772.3 missense
NM_006772.3 missense
Scores
7
11
1
Clinical Significance
Conservation
PhyloP100: 4.15
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNGAP1. . Gene score misZ: 5.6047 (greater than the threshold 3.09). Trascript score misZ: 7.6762 (greater than threshold 3.09). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. GenCC has associacion of the gene with autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.837
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNGAP1 | NM_006772.3 | c.1465C>T | p.Leu489Phe | missense_variant | 9/19 | ENST00000646630.1 | NP_006763.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SYNGAP1 | ENST00000646630.1 | c.1465C>T | p.Leu489Phe | missense_variant | 9/19 | NM_006772.3 | ENSP00000496007.1 | |||
SYNGAP1 | ENST00000644458.1 | c.1465C>T | p.Leu489Phe | missense_variant | 9/19 | ENSP00000495541.1 | ||||
SYNGAP1 | ENST00000449372.7 | c.1465C>T | p.Leu489Phe | missense_variant | 9/18 | 5 | ENSP00000416519.4 | |||
SYNGAP1 | ENST00000418600.7 | c.1465C>T | p.Leu489Phe | missense_variant | 9/19 | 5 | ENSP00000403636.3 | |||
SYNGAP1 | ENST00000645250.1 | c.1288C>T | p.Leu430Phe | missense_variant | 7/17 | ENSP00000494861.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461868Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 exome
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1
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1461868
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35
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1
AN XY:
727240
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Jan 09, 2023 | PP3, PM2_SUP, PP2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;.;M;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;.;D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
.;.;.;D;.;D;D;.
Sift4G
Uncertain
.;D;.;D;D;D;D;.
Polyphen
D;D;.;D;D;D;.;.
Vest4
0.81, 0.79, 0.81
MutPred
Gain of ubiquitination at K492 (P = 0.1472);Gain of ubiquitination at K492 (P = 0.1472);Gain of ubiquitination at K492 (P = 0.1472);Gain of ubiquitination at K492 (P = 0.1472);Gain of ubiquitination at K492 (P = 0.1472);Gain of ubiquitination at K492 (P = 0.1472);.;.;
MVP
0.92
MPC
2.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at