rs774729898

Variant names:

• chr6-33441633-C-T
• rs774729898
• NM_006772.3:c.2168C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_006772.3(SYNGAP1):​c.2168C>T​(p.Thr723Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.797
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13619962).
• BP6: Variant 6-33441633-C-T is Benign according to our data. Variant chr6-33441633-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 436924.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.2168C>T	p.Thr723Ile	missense_variant	Exon 13 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2168C>T	p.Thr723Ile	missense_variant	Exon 13 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.2168C>T	p.Thr723Ile	missense_variant	Exon 13 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.2168C>T	p.Thr723Ile	missense_variant	Exon 13 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.2168C>T	p.Thr723Ile	missense_variant	Exon 13 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1991C>T	p.Thr664Ile	missense_variant	Exon 11 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251210 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 21, 2016

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	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T;.;.;.;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0023
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.;.;L;L;.;.
PhyloP100		0.80
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	.;.;.;N;.;N;N;.
REVEL	Benign	0.045
Sift	Benign	0.13	.;.;.;T;.;T;T;.
Sift4G	Benign	0.17	.;T;.;T;T;T;T;.
Polyphen		0.14	B;B;.;.;B;B;.;.
Vest4		0.22, 0.26, 0.25, 0.20
MutPred		0.35		Loss of phosphorylation at T723 (P = 0.0402);Loss of phosphorylation at T723 (P = 0.0402);Loss of phosphorylation at T723 (P = 0.0402);Loss of phosphorylation at T723 (P = 0.0402);Loss of phosphorylation at T723 (P = 0.0402);Loss of phosphorylation at T723 (P = 0.0402);.;.;
MVP		0.12
MPC		1.2
ClinPred		0.21	T
GERP RS		3.7
Varity_R		0.081
gMVP		0.37
Mutation Taster		=78/22	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: rs774729898; hg19: chr6-33409410;