rs745764103

Variant names:

• chr6-33451852-A-C
• rs745764103
• NM_006772.3:c.3978A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-33451852-A-C
• chr6-33451852-A-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_006772.3(SYNGAP1):​c.3978A>C​(p.Pro1326Pro) 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 0.15 (0 hom., cov: 0)
  • Exomes 𝑓: 0.13 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 6-33451852-A-C is Benign according to our data. Variant chr6-33451852-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 537022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3978A>C	p.Pro1326Pro	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.3978A>C	p.Pro1326Pro	synonymous_variant	Exon 19 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.*50A>C		3_prime_UTR_variant	Exon 19 of 19			ENSP00000495541.1
SYNGAP1	ENST00000418600.7	c.*132A>C		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.*50A>C		3_prime_UTR_variant	Exon 17 of 17			ENSP00000494861.1
SYNGAP1	ENST00000449372.7	c.*50A>C		downstream_gene_variant		5		ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.152 AC: 2294 AN: 15082 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.165

GnomAD2 exomes AF: 0.0490 AC: 2138 AN: 43656 AF XY: 0.0467

Gnomad AFR exome AF: 0.0315

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.0991

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0624

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.132 AC: 26338 AN: 199754 Hom.: 0 Cov.: 23 AF XY: 0.136 AC XY: 14071 AN XY: 103450

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

African (AFR) AF: 0.0899 AC: 387 AN: 4304

American (AMR) AF: 0.118 AC: 726 AN: 6164

Ashkenazi Jewish (ASJ) AF: 0.0834 AC: 420 AN: 5038

East Asian (EAS) AF: 0.0462 AC: 296 AN: 6412

South Asian (SAS) AF: 0.255 AC: 4750 AN: 18650

European-Finnish (FIN) AF: 0.114 AC: 1159 AN: 10192

Middle Eastern (MID) AF: 0.0853 AC: 80 AN: 938

European-Non Finnish (NFE) AF: 0.125 AC: 17473 AN: 139370

Other (OTH) AF: 0.121 AC: 1047 AN: 8686

⚠️ 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: 0.152 AC: 2294 AN: 15104 Hom.: 0 Cov.: 0 AF XY: 0.140 AC XY: 1079 AN XY: 7702

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

African (AFR) AF: 0.144 AC: 622 AN: 4320

American (AMR) AF: 0.0753 AC: 154 AN: 2046

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 65 AN: 324

East Asian (EAS) AF: 0.0558 AC: 24 AN: 430

South Asian (SAS) AF: 0.103 AC: 46 AN: 446

European-Finnish (FIN) AF: 0.101 AC: 150 AN: 1486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.207 AC: 1189 AN: 5754

Other (OTH) AF: 0.163 AC: 39 AN: 240

⚠️ 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: 0.000624 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 07, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Jan 06, 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	-0.66
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		2.1
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: rs745764103; hg19: chr6-33419629; COSMIC: COSV53382168; COSMIC: COSV53382168;