rs1554122390

Variant names:

• chr6-33443928-G-T
• rs1554122390
• NM_006772.3:c.3376G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006772.3(SYNGAP1):​c.3376G>T​(p.Gly1126Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000818 in 1,345,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1126D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24165168).
• BS2: High AC in GnomAdExome4 at 11 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006772.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.3376G>T	p.Gly1126Cys	missense	Exon 15 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.3334G>T	p.Gly1112Cys	missense	Exon 14 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.329+2678C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3376G>T	p.Gly1126Cys	missense	Exon 15 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.3376G>T	p.Gly1126Cys	missense	Exon 15 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.3334G>T	p.Gly1112Cys	missense	Exon 14 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000818 AC: 11 AN: 1345250 Hom.: 0 Cov.: 37 AF XY: 0.0000107 AC XY: 7 AN XY: 656158

African (AFR) AF: 0.00 AC: 0 AN: 30036

American (AMR) AF: 0.00 AC: 0 AN: 26708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19472

East Asian (EAS) AF: 0.00 AC: 0 AN: 38086

South Asian (SAS) AF: 0.0000146 AC: 1 AN: 68262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4524

European-Non Finnish (NFE) AF: 0.00000947 AC: 10 AN: 1056316

Other (OTH) AF: 0.00 AC: 0 AN: 55282

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal dominant 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.45
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0050	B
Vest4		0.42
MutPred		0.35		Loss of ubiquitination at K1130 (P = 0.057)
MVP		0.40
MPC		2.3
ClinPred		0.47	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.60
Mutation Taster		=93/7	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: rs1554122390; hg19: chr6-33411705;