6-33438497-C-T

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

Scores

7
11
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.15
Variant links:
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]
SYNGAP1-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

Genome browser will be placed here

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
SYNGAP1NM_006772.3 linkc.1465C>T p.Leu489Phe missense_variant 9/19 ENST00000646630.1 NP_006763.2 Q96PV0-1A0A1U9X8L0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SYNGAP1ENST00000646630.1 linkc.1465C>T p.Leu489Phe missense_variant 9/19 NM_006772.3 ENSP00000496007.1 Q96PV0-1
SYNGAP1ENST00000644458.1 linkc.1465C>T p.Leu489Phe missense_variant 9/19 ENSP00000495541.1 A0A2R8Y6T2
SYNGAP1ENST00000449372.7 linkc.1465C>T p.Leu489Phe missense_variant 9/185 ENSP00000416519.4 B7ZCA0
SYNGAP1ENST00000418600.7 linkc.1465C>T p.Leu489Phe missense_variant 9/195 ENSP00000403636.3 Q96PV0-2
SYNGAP1ENST00000645250.1 linkc.1288C>T p.Leu430Phe missense_variant 7/17 ENSP00000494861.1 A0A2R8YDS2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461868
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
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 submitterclinical testingAmbry GeneticsSep 01, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenJan 09, 2023PP3, PM2_SUP, PP2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D;D;.;.;.;.;.;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Pathogenic
3.1
M;M;.;.;M;M;.;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.7
.;.;.;D;.;D;D;.
REVEL
Pathogenic
0.72
Sift
Uncertain
0.021
.;.;.;D;.;D;D;.
Sift4G
Uncertain
0.0030
.;D;.;D;D;D;D;.
Polyphen
1.0
D;D;.;D;D;D;.;.
Vest4
0.81, 0.79, 0.81
MutPred
0.76
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
0.99
D
GERP RS
5.1
Varity_R
0.44
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554121340; hg19: chr6-33406274; API