rs72887798

chr6-33438523-T-C

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.1491T>C(p.Tyr497=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,048 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (25 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.21

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=-0.69).
• BP6: Variant 6-33438523-T-C is Benign according to our data. Variant chr6-33438523-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 240704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33438523-T-C is described in Lovd as [Likely_benign]. Variant chr6-33438523-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (613/152192) while in subpopulation NFE AF= 0.00659 (448/68004). AF 95% confidence interval is 0.00608. There are 2 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 614 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.1491T>C	p.Tyr497=	synonymous_variant	9/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.330-1042A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1491T>C	p.Tyr497=	synonymous_variant	9/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.378-1042A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 614 AN: 152074 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00659

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00433 AC: 1090 AN: 251468 Hom.: 7 AF XY: 0.00441 AC XY: 600 AN XY: 135910

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00655

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00526 AC: 7693 AN: 1461856 Hom.: 25 Cov.: 35 AF XY: 0.00515 AC XY: 3744 AN XY: 727230

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.00270

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152192 Hom.: 2 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74422

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00659

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00607 Hom.: 3

Bravo AF: 0.00390

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 31, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNGAP1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 12, 2020

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	6.1
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72887798; hg19: chr6-33406300; COSMIC: COSV53378700; COSMIC: COSV53378700;