6-33435225-G-T

Variant names:

• chr6-33435225-G-T
• NM_006772.3:c.583G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_006772.3(SYNGAP1):​c.583G>T​(p.Ala195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A195P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain PH (size 101) in uniprot entity SYGP1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) 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 chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2614117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.583G>T	p.Ala195Ser	missense_variant	Exon 6 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.583G>T	p.Ala195Ser	missense_variant	Exon 6 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.583G>T	p.Ala195Ser	missense_variant	Exon 6 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.583G>T	p.Ala195Ser	missense_variant	Exon 6 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.583G>T	p.Ala195Ser	missense_variant	Exon 6 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.406G>T	p.Ala136Ser	missense_variant	Exon 4 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461630 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727118

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T;T;.;.;.;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;.;L;L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	.;.;.;N;.;N;N;.
REVEL	Benign	0.078
Sift	Benign	0.26	.;.;.;T;.;T;T;.
Sift4G	Benign	0.19	.;T;.;T;T;T;T;.
Polyphen		0.99	D;D;.;P;D;.;.;.
Vest4		0.40, 0.32, 0.40, 0.38
MutPred		0.19		Gain of phosphorylation at A195 (P = 0.0175);Gain of phosphorylation at A195 (P = 0.0175);Gain of phosphorylation at A195 (P = 0.0175);Gain of phosphorylation at A195 (P = 0.0175);Gain of phosphorylation at A195 (P = 0.0175);Gain of phosphorylation at A195 (P = 0.0175);.;.;
MVP		0.14
MPC		1.5
ClinPred		0.93	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33403002;