rs1060503387

Positions:

• chr6-33443130-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_006772.3(SYNGAP1):​c.2578G>A​(p.Val860Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.90

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

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNGAP1. . Gene score misZ 5.6047 (greater than the threshold 3.09). Trascript score misZ 7.6762 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.12670788).
• BP6: Variant 6-33443130-G-A is Benign according to our data. Variant chr6-33443130-G-A is described in ClinVar as [Benign]. Clinvar id is 411591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.2578G>A	p.Val860Ile	missense_variant	15/19	ENST00000646630.1	NP_006763.2
SYNGAP1-AS1	NR_174954.1	n.329+3476C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2578G>A	p.Val860Ile	missense_variant	15/19		NM_006772.3	ENSP00000496007	P1
SYNGAP1-AS1	ENST00000630418.1	n.377+3476C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

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: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;T;.;.;.;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.;.;N;N;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.35	.;.;.;N;.;N;N;.
REVEL	Benign	0.039
Sift	Benign	0.15	.;.;.;T;.;T;T;.
Sift4G	Benign	0.65	.;T;.;T;T;T;T;.
Polyphen		0.0090	B;B;.;.;B;B;.;.
Vest4		0.089, 0.10, 0.11, 0.10
MutPred		0.080		Gain of glycosylation at S859 (P = 0.1356);Gain of glycosylation at S859 (P = 0.1356);Gain of glycosylation at S859 (P = 0.1356);.;Gain of glycosylation at S859 (P = 0.1356);Gain of glycosylation at S859 (P = 0.1356);.;.;
MVP		0.26
MPC		0.95
ClinPred		0.42	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1060503387; hg19: chr6-33410907;