rs753575634

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_006772.3(SYNGAP1):​c.2864C>T​(p.Ser955Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

SYNGAP1
NM_006772.3 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.45
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 Likely_benign. Variant got -6 ACMG points.

PP2
Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
BP4
Computational evidence support a benign effect (MetaRNN=0.17859203).
BP6
Variant 6-33443416-C-T is Benign according to our data. Variant chr6-33443416-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444679.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}. Variant chr6-33443416-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNGAP1NM_006772.3 linkc.2864C>T p.Ser955Phe missense_variant Exon 15 of 19 ENST00000646630.1 NP_006763.2 Q96PV0-1A0A1U9X8L0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNGAP1ENST00000646630.1 linkc.2864C>T p.Ser955Phe missense_variant Exon 15 of 19 NM_006772.3 ENSP00000496007.1 Q96PV0-1
SYNGAP1ENST00000644458.1 linkc.2864C>T p.Ser955Phe missense_variant Exon 15 of 19 ENSP00000495541.1 A0A2R8Y6T2
SYNGAP1ENST00000449372.7 linkc.2822C>T p.Ser941Phe missense_variant Exon 14 of 18 5 ENSP00000416519.4 B7ZCA0
SYNGAP1ENST00000418600.7 linkc.2864C>T p.Ser955Phe missense_variant Exon 15 of 19 5 ENSP00000403636.3 Q96PV0-2
SYNGAP1ENST00000645250.1 linkc.2687C>T p.Ser896Phe missense_variant Exon 13 of 17 ENSP00000494861.1 A0A2R8YDS2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152118
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251192
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135822
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000595
AC:
87
AN:
1461776
Hom.:
0
Cov.:
33
AF XY:
0.0000591
AC XY:
43
AN XY:
727206
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:
0.0000764
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152118
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000967
Hom.:
0
Bravo
AF:
0.0000491
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Aug 16, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jul 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SYNGAP1: PP2, BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.080
T;T;.;.;.;.;.;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.90
.;D;D;D;D;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.18
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;L;.;.;L;L;.;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.7
.;.;.;N;.;N;N;.
REVEL
Benign
0.093
Sift
Uncertain
0.0010
.;.;.;D;.;D;D;.
Sift4G
Benign
0.14
.;T;.;T;T;T;T;.
Polyphen
0.98
D;D;.;.;D;D;.;.
Vest4
0.29, 0.28, 0.36, 0.28
MVP
0.18
MPC
2.3
ClinPred
0.43
T
GERP RS
4.4
Varity_R
0.11
gMVP
0.32

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: rs753575634; hg19: chr6-33411193; API