rs875989808

Positions:

• chr6-33444529-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_006772.3(SYNGAP1):​c.3494C>T​(p.Ser1165Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.40

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SYGP1_HUMAN
• 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). GenCC has associacion of 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.
• PP5: Variant 6-33444529-C-T is Pathogenic according to our data. Variant chr6-33444529-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225899.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr6-33444529-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.30060458). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3494C>T	p.Ser1165Leu	missense_variant	16/19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3494C>T	p.Ser1165Leu	missense_variant	16/19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.3494C>T	p.Ser1165Leu	missense_variant	16/19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.3452C>T	p.Ser1151Leu	missense_variant	15/18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.3494C>T	p.Ser1165Leu	missense_variant	16/19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.3317C>T	p.Ser1106Leu	missense_variant	14/17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	literature only	Center for Human Genetics, University of Leuven	Jan 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SYNGAP1 function (PMID: 33308442). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SYNGAP1 protein function. ClinVar contains an entry for this variant (Variation ID: 225899). This missense change has been observed in individual(s) with intellectual disability (PMID: 27159028). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1165 of the SYNGAP1 protein (p.Ser1165Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;T;.;.;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L;L;.;.;L;L;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	.;.;.;N;.;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.39	.;.;.;T;.;T;T;.
Sift4G	Benign	0.21	.;T;.;T;T;T;T;.
Polyphen		1.0	D;D;.;.;D;D;.;.
Vest4		0.63, 0.83, 0.55, 0.59
MutPred		0.34		Gain of catalytic residue at S1165 (P = 0.0028);Gain of catalytic residue at S1165 (P = 0.0028);Gain of catalytic residue at S1165 (P = 0.0028);.;Gain of catalytic residue at S1165 (P = 0.0028);Gain of catalytic residue at S1165 (P = 0.0028);.;.;
MVP		0.34
MPC		2.2
ClinPred		0.95	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.73

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

Other links and lift over

dbSNP: rs875989808; hg19: chr6-33412306;