rs751387116

Positions:

• chr6-33451846-A-C
• chr6-33451846-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_006772.3(SYNGAP1):​c.3972A>C​(p.Pro1324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (0 hom., cov: 0)
  • Exomes 𝑓: 0.27 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.189

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 6-33451846-A-C is Benign according to our data. Variant chr6-33451846-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 537023.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.189 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3972A>C	p.Pro1324=	synonymous_variant	19/19	ENST00000646630.1	NP_006763.2
SYNGAP1-AS1	NR_174954.1	n.136+2424T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3972A>C	p.Pro1324=	synonymous_variant	19/19		NM_006772.3	ENSP00000496007	P1
SYNGAP1-AS1	ENST00000630418.1	n.184+2424T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2636 AN: 23070 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0946

Gnomad AMR AF: 0.0713

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.273 AC: 72337 AN: 264912 Hom.: 0 Cov.: 21 AF XY: 0.263 AC XY: 35451 AN XY: 134898

Gnomad4 AFR exome AF: 0.243

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.252

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.303

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.114 AC: 2635 AN: 23098 Hom.: 0 Cov.: 0 AF XY: 0.109 AC XY: 1245 AN XY: 11444

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0713

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.0381

Gnomad4 SAS AF: 0.0893

Gnomad4 FIN AF: 0.0996

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.129

Alfa AF: 0.00119 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.8
DANN	Benign	0.57

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: rs751387116; hg19: chr6-33419623; COSMIC: COSV105124041; COSMIC: COSV105124041;