chrX-47574336-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006950.3(SYN1):c.1648G>A(p.Ala550Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,042,104 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A550F) has been classified as Uncertain significance.
Frequency
Consequence
NM_006950.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SYN1 | NM_006950.3 | c.1648G>A | p.Ala550Thr | missense_variant | 12/13 | ENST00000295987.13 | |
SYN1 | NM_133499.2 | c.1648G>A | p.Ala550Thr | missense_variant | 12/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SYN1 | ENST00000295987.13 | c.1648G>A | p.Ala550Thr | missense_variant | 12/13 | 2 | NM_006950.3 | P3 | |
SYN1 | ENST00000340666.5 | c.1648G>A | p.Ala550Thr | missense_variant | 12/13 | 1 | A1 | ||
SYN1 | ENST00000640721.1 | c.70+352G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000455 AC: 5AN: 109930Hom.: 0 Cov.: 23 AF XY: 0.0000303 AC XY: 1AN XY: 32954
GnomAD4 exome AF: 0.0000225 AC: 21AN: 932174Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 2AN XY: 290248
GnomAD4 genome ? AF: 0.0000455 AC: 5AN: 109930Hom.: 0 Cov.: 23 AF XY: 0.0000303 AC XY: 1AN XY: 32954
ClinVar
Submissions by phenotype
Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 15, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SYN1 function (PMID: 21441247, 26173895). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 41889). This variant is also known as p.Ala548Thr. This missense change has been observed in individuals with SYN1-related conditions (PMID: 21441247; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 550 of the SYN1 protein (p.Ala550Thr). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2023 | Variant summary: SYN1 c.1648G>A (p.Ala550Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 17090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1648G>A has been reported in the literature in individuals affected with epilepsy, autism spectrum disorder, and schizophrenia (examples: Fassio_2011, and Mojarad_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders. Experimental studies have reported the variant affects normal protein function however is insufficient to determine the role of this variant in disease (examples: Fassio_2011, and Tang_2014). The following publications have been ascertained in the context of this evaluation (PMID: 21441247, 33526774, 26173895). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
SYN1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 08, 2024 | The SYN1 c.1648G>A variant is predicted to result in the amino acid substitution p.Ala550Thr. This variant has been reported to be causative for autism spectrum disorders with or without epilepsy in four unrelated French Canadian patients (Fassio et al. 2011 et al. PubMed ID: 21441247). Functional studies showed that this variant displayed impaired targeting to nerve terminals (Fassio et al. 2011 et al. PubMed ID: 21441247; Tang et al. 2015. PubMed ID: 26173895, reported as A548T). This variant has not been reported in a large population database, indicating this variant is rare. However, it has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41889/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at