6-33443723-C-T

Variant names:

• chr6-33443723-C-T
• rs761405990
• NM_006772.3:c.3171C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006772.3(SYNGAP1):​c.3171C>T​(p.Ser1057Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000321 in 655,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-33443723-C-T is Benign according to our data. Variant chr6-33443723-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 19 AD,Unknown gene.

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.3171C>T	p.Ser1057Ser	synonymous	Exon 15 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.3129C>T	p.Ser1043Ser	synonymous	Exon 14 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.329+2883G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3171C>T	p.Ser1057Ser	synonymous	Exon 15 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.3171C>T	p.Ser1057Ser	synonymous	Exon 15 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.3129C>T	p.Ser1043Ser	synonymous	Exon 14 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.0000141 AC: 2 AN: 141548 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000264

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000125 AC: 3 AN: 239462 AF XY: 0.00000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 19 AN: 513626 Hom.: 0 Cov.: 27 AF XY: 0.0000361 AC XY: 10 AN XY: 276640

African (AFR) AF: 0.0000741 AC: 1 AN: 13494

American (AMR) AF: 0.00 AC: 0 AN: 36314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12558

East Asian (EAS) AF: 0.00 AC: 0 AN: 14454

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69496

European-Finnish (FIN) AF: 0.0000643 AC: 2 AN: 31094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3114

European-Non Finnish (NFE) AF: 0.0000417 AC: 13 AN: 312036

Other (OTH) AF: 0.0000949 AC: 2 AN: 21066

GnomAD4 genome AF: 0.0000141 AC: 2 AN: 141548 Hom.: 0 Cov.: 31 AF XY: 0.0000291 AC XY: 2 AN XY: 68666

African (AFR) AF: 0.0000251 AC: 1 AN: 39802

American (AMR) AF: 0.00 AC: 0 AN: 14414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.00 AC: 0 AN: 4010

South Asian (SAS) AF: 0.000264 AC: 1 AN: 3788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64258

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.2
DANN	Benign	0.42
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs761405990; hg19: chr6-33411500;