rs72887798

Variant names:

• chr6-33438523-T-C
• rs72887798
• NM_006772.3:c.1491T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006772.3(SYNGAP1):​c.1491T>C​(p.Tyr497Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,048 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (25 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.21
• Publications: 2 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)

MIR5004 (HGNC:43532): (microRNA 5004) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 6-33438523-T-C is Benign according to our data. Variant chr6-33438523-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00403 (613/152192) while in subpopulation NFE AF = 0.00659 (448/68004). AF 95% confidence interval is 0.00608. There are 2 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 613 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.1491T>C	p.Tyr497Tyr	synonymous	Exon 9 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.1491T>C	p.Tyr497Tyr	synonymous	Exon 9 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.330-1042A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.1491T>C	p.Tyr497Tyr	synonymous	Exon 9 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.1491T>C	p.Tyr497Tyr	synonymous	Exon 9 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.1491T>C	p.Tyr497Tyr	synonymous	Exon 9 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 614 AN: 152074 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00659

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00433 AC: 1090 AN: 251468 AF XY: 0.00441

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00655

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00526 AC: 7693 AN: 1461856 Hom.: 25 Cov.: 35 AF XY: 0.00515 AC XY: 3744 AN XY: 727230

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 387 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86254

European-Finnish (FIN) AF: 0.00270 AC: 144 AN: 53408

Middle Eastern (MID) AF: 0.00940 AC: 54 AN: 5746

European-Non Finnish (NFE) AF: 0.00590 AC: 6562 AN: 1112012

Other (OTH) AF: 0.00545 AC: 329 AN: 60396

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152192 Hom.: 2 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74422

African (AFR) AF: 0.000795 AC: 33 AN: 41508

American (AMR) AF: 0.00294 AC: 45 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00659 AC: 448 AN: 68004

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00607 Hom.: 3

Bravo AF: 0.00390

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00563

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Intellectual disability, autosomal dominant 5 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.1
DANN	Benign	0.79
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72887798; hg19: chr6-33406300; COSMIC: COSV53378700; COSMIC: COSV53378700;