rs61421477

Variant names:

• chr6-33443522-C-T
• rs61421477
• NM_006772.3:c.2970C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006772.3(SYNGAP1):​c.2970C>T​(p.Ser990Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,614,142 control chromosomes in the GnomAD database, including 1,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (541 hom., cov: 32)
  • Exomes 𝑓: 0.016 (625 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.340
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 6-33443522-C-T is Benign according to our data. Variant chr6-33443522-C-T is described in ClinVar as Benign. ClinVar VariationId is 130529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

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.2970C>T	p.Ser990Ser	synonymous	Exon 15 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.2928C>T	p.Ser976Ser	synonymous	Exon 14 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.329+3084G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.2970C>T	p.Ser990Ser	synonymous	Exon 15 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.2970C>T	p.Ser990Ser	synonymous	Exon 15 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.2928C>T	p.Ser976Ser	synonymous	Exon 14 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8253 AN: 152156 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00751

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0593

GnomAD2 exomes AF: 0.0239 AC: 5998 AN: 251362 AF XY: 0.0211

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00527

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0159 AC: 23227 AN: 1461868 Hom.: 625 Cov.: 33 AF XY: 0.0155 AC XY: 11296 AN XY: 727232

African (AFR) AF: 0.159 AC: 5322 AN: 33480

American (AMR) AF: 0.0263 AC: 1174 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 682 AN: 26136

East Asian (EAS) AF: 0.00310 AC: 123 AN: 39700

South Asian (SAS) AF: 0.0166 AC: 1429 AN: 86256

European-Finnish (FIN) AF: 0.00258 AC: 138 AN: 53414

Middle Eastern (MID) AF: 0.0728 AC: 420 AN: 5768

European-Non Finnish (NFE) AF: 0.0111 AC: 12330 AN: 1111996

Other (OTH) AF: 0.0266 AC: 1609 AN: 60396

GnomAD4 genome AF: 0.0543 AC: 8275 AN: 152274 Hom.: 541 Cov.: 32 AF XY: 0.0519 AC XY: 3861 AN XY: 74452

African (AFR) AF: 0.157 AC: 6496 AN: 41504

American (AMR) AF: 0.0325 AC: 497 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3470

East Asian (EAS) AF: 0.00714 AC: 37 AN: 5180

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4830

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10624

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 896 AN: 68036

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0360 Hom.: 164

Bravo AF: 0.0630

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0181

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs61421477; hg19: chr6-33411299; COSMIC: COSV53385570; COSMIC: COSV53385570;