rs764031180

Variant names:

• chr6-33451843-A-C
• rs764031180
• NM_006772.3:c.3969A>C
• SYNGAP1 p.Pro1323Pro

Your query was ambiguous. Multiple possible variants found:

• chr6-33451843-A-C
• chr6-33451843-A-G

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.3969A>C​(p.Pro1323Pro) 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 0.12 (0 hom., cov: 0)
  • Exomes 𝑓: 0.33 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.396
• Publications: 0 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=-0.68).
• BP6: Variant 6-33451843-A-C is Benign according to our data. Variant chr6-33451843-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 537011.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.396 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006772.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.3969A>C	p.Pro1323Pro	synonymous	Exon 19 of 19	NP_006763.2	A0A1U9X8L0
	SYNGAP1	NM_001130066.2		c.*41A>C		3_prime_UTR	Exon 18 of 18	NP_001123538.1	B7ZCA0
	SYNGAP1-AS1	NR_174954.1		n.136+2427T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3969A>C	p.Pro1323Pro	synonymous	Exon 19 of 19	ENSP00000496007.1	Q96PV0-1
	SYNGAP1	ENST00000644458.1		c.*41A>C		3_prime_UTR	Exon 19 of 19	ENSP00000495541.1	A0A2R8Y6T2
	SYNGAP1	ENST00000418600.7	TSL:5	c.*123A>C		3_prime_UTR	Exon 19 of 19	ENSP00000403636.3	Q96PV0-2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 2816 AN: 24056 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0784

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.0929

Gnomad FIN AF: 0.0964

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.0694 AC: 3143 AN: 45268 AF XY: 0.0669

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.0676

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0925

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.331 AC: 88747 AN: 267954 Hom.: 0 Cov.: 21 AF XY: 0.323 AC XY: 42874 AN XY: 132836

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

African (AFR) AF: 0.310 AC: 1626 AN: 5248

American (AMR) AF: 0.211 AC: 1317 AN: 6238

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 991 AN: 4602

East Asian (EAS) AF: 0.158 AC: 778 AN: 4912

South Asian (SAS) AF: 0.310 AC: 6165 AN: 19884

European-Finnish (FIN) AF: 0.141 AC: 1418 AN: 10034

Middle Eastern (MID) AF: 0.215 AC: 200 AN: 930

European-Non Finnish (NFE) AF: 0.355 AC: 73062 AN: 205856

Other (OTH) AF: 0.311 AC: 3190 AN: 10250

⚠️ 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: 0.117 AC: 2817 AN: 24088 Hom.: 0 Cov.: 0 AF XY: 0.114 AC XY: 1342 AN XY: 11814

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

African (AFR) AF: 0.116 AC: 772 AN: 6668

American (AMR) AF: 0.0786 AC: 216 AN: 2748

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 82 AN: 582

East Asian (EAS) AF: 0.0444 AC: 26 AN: 586

South Asian (SAS) AF: 0.0924 AC: 58 AN: 628

European-Finnish (FIN) AF: 0.0964 AC: 189 AN: 1960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.136 AC: 1424 AN: 10444

Other (OTH) AF: 0.115 AC: 42 AN: 366

⚠️ 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: 0.00173 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal dominant 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.6
DANN	Benign	0.59
PhyloP100		0.40
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs764031180;

hg19: chr6-33419620;

COSMIC: COSV53382165;

COSMIC: COSV53382165;