rs751387116

Variant names:

• chr6-33451846-A-C
• rs751387116
• NM_006772.3:c.3972A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_006772.3(SYNGAP1):​c.3972A>C​(p.Pro1324Pro) 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
• Publications: 1 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 (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 VariationId 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 rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3972A>C	p.Pro1324Pro	synonymous_variant	Exon 19 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3972A>C	p.Pro1324Pro	synonymous_variant	Exon 19 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.*44A>C		3_prime_UTR_variant	Exon 19 of 19			ENSP00000495541.1
SYNGAP1	ENST00000418600.7	c.*126A>C		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.*44A>C		3_prime_UTR_variant	Exon 17 of 17			ENSP00000494861.1
SYNGAP1	ENST00000449372.7	c.*44A>C		downstream_gene_variant		5		ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.114 AC: 2636 AN: 23070 Hom.: 0 Cov.: 0

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

GnomAD2 exomes AF: 0.0442 AC: 2688 AN: 60834 AF XY: 0.0420

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.0855

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0607

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.243 AC: 1280 AN: 5268

American (AMR) AF: 0.145 AC: 1080 AN: 7430

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 823 AN: 5710

East Asian (EAS) AF: 0.111 AC: 583 AN: 5230

South Asian (SAS) AF: 0.252 AC: 5958 AN: 23614

European-Finnish (FIN) AF: 0.100 AC: 1273 AN: 12674

Middle Eastern (MID) AF: 0.141 AC: 155 AN: 1098

European-Non Finnish (NFE) AF: 0.303 AC: 58580 AN: 193494

Other (OTH) AF: 0.251 AC: 2605 AN: 10394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.111 AC: 696 AN: 6288

American (AMR) AF: 0.0713 AC: 187 AN: 2624

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 77 AN: 536

East Asian (EAS) AF: 0.0381 AC: 25 AN: 656

South Asian (SAS) AF: 0.0893 AC: 62 AN: 694

European-Finnish (FIN) AF: 0.0996 AC: 183 AN: 1838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.135 AC: 1354 AN: 10018

Other (OTH) AF: 0.129 AC: 44 AN: 342

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.8
DANN	Benign	0.57
PhyloP100		-0.19
Mutation Taster		=100/0	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: rs751387116; hg19: chr6-33419623; COSMIC: COSV105124041; COSMIC: COSV105124041;