6-33451831-C-T

Variant names:

• chr6-33451831-C-T
• rs773538561
• NM_006772.3:c.3957C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006772.3(SYNGAP1):​c.3957C>T​(p.Ala1319Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000045 in 1,555,590 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 (★). Synonymous variant affecting the same amino acid position (i.e. A1319A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.62
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-33451831-C-T is Benign according to our data. Variant chr6-33451831-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2963307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.3957C>T	p.Ala1319Ala	synonymous_variant	Exon 19 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3957C>T	p.Ala1319Ala	synonymous_variant	Exon 19 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.*29C>T		3_prime_UTR_variant	Exon 19 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.*29C>T		3_prime_UTR_variant	Exon 18 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.*111C>T		3_prime_UTR_variant	Exon 19 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.*29C>T		3_prime_UTR_variant	Exon 17 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150870 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000489

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

GnomAD2 exomes AF: 0.0000172 AC: 3 AN: 174546 AF XY: 0.0000211

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000622

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1404720 Hom.: 0 Cov.: 31 AF XY: 0.00000432 AC XY: 3 AN XY: 695126

African (AFR) AF: 0.00 AC: 0 AN: 32126

American (AMR) AF: 0.00 AC: 0 AN: 38360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25300

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36974

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80366

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079724

Other (OTH) AF: 0.00 AC: 0 AN: 58072

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150870 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73570

African (AFR) AF: 0.0000489 AC: 2 AN: 40912

American (AMR) AF: 0.00 AC: 0 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67694

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Benign:1

Jan 24, 2024

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
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		3.6

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: rs773538561; hg19: chr6-33419608;