rs1554121685

Variant names:

• chr6-33440770-G-A
• rs1554121685
• NM_006772.3:c.1718G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-33440770-G-A
• chr6-33440770-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_006772.3(SYNGAP1):​c.1718G>A​(p.Arg573Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R573W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.86
• 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_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 8 uncertain in NM_006772.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-33440769-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421734.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 6-33440770-G-A is Pathogenic according to our data. Variant chr6-33440770-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1176819.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.1718G>A	p.Arg573Gln	missense_variant	Exon 11 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1718G>A	p.Arg573Gln	missense_variant	Exon 11 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.1718G>A	p.Arg573Gln	missense_variant	Exon 11 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.1718G>A	p.Arg573Gln	missense_variant	Exon 11 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.1718G>A	p.Arg573Gln	missense_variant	Exon 11 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1541G>A	p.Arg514Gln	missense_variant	Exon 9 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.3	M;M;.;.;M;M;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	.;.;.;D;.;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.014	.;.;.;D;.;D;D;.
Sift4G	Uncertain	0.0090	.;D;.;T;T;T;D;.
Polyphen		1.0	D;D;.;.;D;D;.;.
Vest4		0.60, 0.63, 0.65, 0.63
MutPred		0.71		Loss of MoRF binding (P = 0.0674);Loss of MoRF binding (P = 0.0674);Loss of MoRF binding (P = 0.0674);Loss of MoRF binding (P = 0.0674);Loss of MoRF binding (P = 0.0674);Loss of MoRF binding (P = 0.0674);.;.;
MVP		0.84
MPC		2.5
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.86
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: 2

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

Other links and lift over

dbSNP: rs1554121685; hg19: chr6-33408547;