chr6-33443723-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006772.3(SYNGAP1):​c.3171C>G​(p.Ser1057Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1057N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08156276).

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>G	p.Ser1057Arg	missense	Exon 15 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.3129C>G	p.Ser1043Arg	missense	Exon 14 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.329+2883G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.3171C>G	p.Ser1057Arg	missense	Exon 15 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.3171C>G	p.Ser1057Arg	missense	Exon 15 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.3129C>G	p.Ser1043Arg	missense	Exon 14 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 141538 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000195 AC: 1 AN: 512816 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 276216

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

African (AFR) AF: 0.00 AC: 0 AN: 13460

American (AMR) AF: 0.00 AC: 0 AN: 36292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12532

East Asian (EAS) AF: 0.00 AC: 0 AN: 14396

South Asian (SAS) AF: 0.00 AC: 0 AN: 69490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3110

European-Non Finnish (NFE) AF: 0.00000321 AC: 1 AN: 311446

Other (OTH) AF: 0.00 AC: 0 AN: 21024

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 141684 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68784

African (AFR) AF: 0.00 AC: 0 AN: 39892

American (AMR) AF: 0.00 AC: 0 AN: 14442

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4008

South Asian (SAS) AF: 0.00 AC: 0 AN: 3808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64260

Other (OTH) AF: 0.00 AC: 0 AN: 2024

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	1.8
DANN	Benign	0.92
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		0.68	P
Vest4		0.22
MutPred		0.31		Gain of methylation at S1057 (P = 8e-04)
MVP		0.48
MPC		1.4
ClinPred		0.15	T
GERP RS		-6.3
Varity_R		0.058
gMVP		0.33
Mutation Taster		=97/3	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: rs761405990; hg19: chr6-33411500;