rs139841529

chr6-33443876-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006772.3(SYNGAP1):c.3324C>T(p.Ser1108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,522,264 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0230

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-33443876-C-T is Benign according to our data. Variant chr6-33443876-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33443876-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.023 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000889 (135/151918) while in subpopulation SAS AF= 0.00916 (44/4806). AF 95% confidence interval is 0.00701. There are 2 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 137 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.3324C>T	p.Ser1108=	synonymous_variant	15/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.329+2730G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3324C>T	p.Ser1108=	synonymous_variant	15/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.377+2730G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 137 AN: 151806 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00252

Gnomad SAS AF: 0.00936

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00166 AC: 283 AN: 170950 Hom.: 0 AF XY: 0.00181 AC XY: 166 AN XY: 91964

Gnomad AFR exome AF: 0.000293

Gnomad AMR exome AF: 0.000220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00146

Gnomad SAS exome AF: 0.00968

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00118 AC: 1621 AN: 1370346 Hom.: 18 Cov.: 64 AF XY: 0.00137 AC XY: 920 AN XY: 670976

Gnomad4 AFR exome AF: 0.000229

Gnomad4 AMR exome AF: 0.000219

Gnomad4 ASJ exome AF: 0.0000492

Gnomad4 EAS exome AF: 0.000851

Gnomad4 SAS exome AF: 0.00872

Gnomad4 FIN exome AF: 0.0000614

Gnomad4 NFE exome AF: 0.000758

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.000889 AC: 135 AN: 151918 Hom.: 2 Cov.: 31 AF XY: 0.00108 AC XY: 80 AN XY: 74246

Gnomad4 AFR AF: 0.000242

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.00916

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000599 Hom.: 0

Bravo AF: 0.000695

Asia WGS AF: 0.00434 AC: 15 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SYNGAP1: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 25, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2016

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. -

Intellectual disability, autosomal dominant 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	9.9
Dann	Benign	0.64

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: rs139841529; hg19: chr6-33411653;