chr6-33438440-A-C

Variant names:

• chr6-33438440-A-C
• rs1554121320
• NM_006772.3:c.1408A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP2 PP3 BP6_Moderate

The NM_006772.3(SYNGAP1):​c.1408A>C​(p.Met470Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.32

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• BP6: Variant 6-33438440-A-C is Benign according to our data. Variant chr6-33438440-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 536996.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.1408A>C	p.Met470Leu	missense_variant	Exon 9 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1408A>C	p.Met470Leu	missense_variant	Exon 9 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.1408A>C	p.Met470Leu	missense_variant	Exon 9 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.1408A>C	p.Met470Leu	missense_variant	Exon 9 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.1408A>C	p.Met470Leu	missense_variant	Exon 9 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1231A>C	p.Met411Leu	missense_variant	Exon 7 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D;D;.;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.088	D
MutationAssessor	Benign	1.9	L;L;.;.;L;L;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	.;.;.;D;.;D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	.;.;.;D;.;D;D;.
Sift4G	Uncertain	0.0070	.;D;.;D;D;D;D;.
Polyphen		0.84	P;P;.;B;P;P;.;.
Vest4		0.53, 0.55, 0.50, 0.55
MutPred		0.56		Loss of catalytic residue at M470 (P = 0.0087);Loss of catalytic residue at M470 (P = 0.0087);Loss of catalytic residue at M470 (P = 0.0087);Loss of catalytic residue at M470 (P = 0.0087);Loss of catalytic residue at M470 (P = 0.0087);Loss of catalytic residue at M470 (P = 0.0087);.;.;
MVP		0.75
MPC		2.2
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554121320; hg19: chr6-33406217;