rs749376396

Positions:

• chr6-33451787-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_006772.3(SYNGAP1):​c.3913A>G​(p.Thr1305Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.67

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 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=0.02316174).
• BP6: Variant 6-33451787-A-G is Benign according to our data. Variant chr6-33451787-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411587.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000329 (5/152004) while in subpopulation AMR AF= 0.000328 (5/15262). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3913A>G	p.Thr1305Ala	missense_variant	19/19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3913A>G	p.Thr1305Ala	missense_variant	19/19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.3912A>G	p.Gln1304Gln	synonymous_variant	19/19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.3864A>G	p.Gln1288Gln	synonymous_variant	18/18	5		ENSP00000416519.4
SYNGAP1	ENST00000645250.1	c.3735A>G	p.Gln1245Gln	synonymous_variant	17/17			ENSP00000494861.1
SYNGAP1	ENST00000418600.7	c.*67A>G		3_prime_UTR_variant	19/19	5		ENSP00000403636.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152004 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000723 AC: 18 AN: 249008 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726898

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152004 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74236

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 28, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.027	T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	.;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.9	N;N;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	1.8	.;.;N
REVEL	Benign	0.069
Sift	Benign	1.0	.;.;T
Sift4G	Benign	1.0	.;T;T
Polyphen		0.0	B;B;.
Vest4		0.094, 0.22
MutPred		0.28		Loss of glycosylation at T1305 (P = 0.0238);Loss of glycosylation at T1305 (P = 0.0238);.;
MVP		0.043
ClinPred		0.055	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.28

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: rs749376396; hg19: chr6-33419564;