NM_006772.3:c.3902C>A

Variant names:

• chr6-33451776-C-A
• rs199694815
• NM_006772.3:c.3902C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS2

The NM_006772.3(SYNGAP1):​c.3902C>A​(p.Pro1301His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1301R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.83
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22557682).
• BP6: Variant 6-33451776-C-A is Benign according to our data. Variant chr6-33451776-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212356.
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3902C>A	p.Pro1301His	missense_variant	Exon 19 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3902C>A	p.Pro1301His	missense_variant	Exon 19 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.3901C>A	p.Pro1301Thr	missense_variant	Exon 19 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.3853C>A	p.Pro1285Thr	missense_variant	Exon 18 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000645250.1	c.3724C>A	p.Pro1242Thr	missense_variant	Exon 17 of 17			ENSP00000494861.1
SYNGAP1	ENST00000418600.7	c.*56C>A		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000403636.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Uncertain:1

Apr 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: 212356). This variant has not been reported in the literature in individuals affected with SYNGAP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1301 of the SYNGAP1 protein (p.Pro1301His). -

not specified Benign:1

Mar 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	N;N;.
PhyloP100		6.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.98	.;.;N
REVEL	Benign	0.10
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		0.64	P;P;.
Vest4		0.26, 0.36
MutPred		0.16		Loss of catalytic residue at P1300 (P = 0.0131);Loss of catalytic residue at P1300 (P = 0.0131);.;
MVP		0.068
ClinPred		0.63	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.34
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs199694815; hg19: chr6-33419553;