chr6-33443500-G-A

Variant names:

• chr6-33443500-G-A
• rs1554122267
• NM_006772.3:c.2948G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_006772.3(SYNGAP1):​c.2948G>A​(p.Ser983Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,844 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.33
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29572088).
• BP6: Variant 6-33443500-G-A is Benign according to our data. Variant chr6-33443500-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 469153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.2948G>A	p.Ser983Asn	missense_variant	Exon 15 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2948G>A	p.Ser983Asn	missense_variant	Exon 15 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.2948G>A	p.Ser983Asn	missense_variant	Exon 15 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.2906G>A	p.Ser969Asn	missense_variant	Exon 14 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.2948G>A	p.Ser983Asn	missense_variant	Exon 15 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.2771G>A	p.Ser924Asn	missense_variant	Exon 13 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

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	0.91
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.;L;L;.;.
PhyloP100		6.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	.;.;.;N;.;N;N;.
REVEL	Benign	0.14
Sift	Uncertain	0.024	.;.;.;D;.;D;T;.
Sift4G	Uncertain	0.029	.;D;.;D;D;D;D;.
Polyphen		0.99	D;D;.;.;D;D;.;.
Vest4		0.40, 0.35, 0.58, 0.39
MutPred		0.12		Loss of phosphorylation at S983 (P = 0.0533);Loss of phosphorylation at S983 (P = 0.0533);Loss of phosphorylation at S983 (P = 0.0533);.;Loss of phosphorylation at S983 (P = 0.0533);Loss of phosphorylation at S983 (P = 0.0533);.;.;
MVP		0.60
MPC		2.2
ClinPred		0.69	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.74
Mutation Taster		=72/28	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: rs1554122267; hg19: chr6-33411277;