chr6-33432704-G-T

Variant names:

• chr6-33432704-G-T
• rs759426721
• NM_006772.3:c.407G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006772.3(SYNGAP1):​c.407G>T​(p.Arg136Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000078 in 1,281,836 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.27
• 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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SYNGAP1-related developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.407G>T	p.Arg136Leu	missense_variant	Exon 5 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.407G>T	p.Arg136Leu	missense_variant	Exon 5 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.407G>T	p.Arg136Leu	missense_variant	Exon 5 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.407G>T	p.Arg136Leu	missense_variant	Exon 5 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.407G>T	p.Arg136Leu	missense_variant	Exon 5 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.230G>T	p.Arg77Leu	missense_variant	Exon 3 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.80e-7 AC: 1 AN: 1281836 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 635390

African (AFR) AF: 0.00 AC: 0 AN: 28300

American (AMR) AF: 0.00 AC: 0 AN: 39196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19436

East Asian (EAS) AF: 0.00 AC: 0 AN: 24238

South Asian (SAS) AF: 0.00 AC: 0 AN: 84558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4810

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995586

Other (OTH) AF: 0.00 AC: 0 AN: 48408

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;.;.;M;M;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	.;.;.;D;.;D;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	.;.;.;D;.;D;D;.
Sift4G	Uncertain	0.0020	.;D;.;D;D;D;D;.
Polyphen		0.19	B;B;.;P;B;.;.;.
Vest4		0.57, 0.65, 0.56, 0.54
MutPred		0.23		Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);Loss of methylation at R136 (P = 0.0363);.;.;
MVP		0.23
MPC		1.5
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.84
Mutation Taster		=30/70	disease causing

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: rs759426721; hg19: chr6-33400481;