rs745491762
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS1_Supporting
The NM_007315.4(STAT1):c.1765G>T(p.Ala589Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,614,070 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 Uncertain significance (★★).
Frequency
Consequence
NM_007315.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250204Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135350
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727240
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74350
ClinVar
Submissions by phenotype
Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Uncertain:2
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 589 of the STAT1 protein (p.Ala589Ser). This variant is present in population databases (rs745491762, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 424473). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
This 8 year old male has a history of autism spectrum disorder, myoclonic jerks, coordination disorder, ADHD, disruptive behavior, tachycardia, joint laxity, recurrent rashes, recurrent respiratory illness, and eosinophilic esophagitis. Genetic testing to date, including exome sequencing, has not yielded a diagnosis. The p.Ala589Ser variant in STAT1 is present in the gnomAD African population at a frequency of 0.025%. Computational prediction models are inconsistent. Subsequent clinical testing showed normal neutrophil function studies and quantitative immunoglobulins. -
Inborn genetic diseases Uncertain:1
The c.1765G>T (p.A589S) alteration is located in exon 21 (coding exon 19) of the STAT1 gene. This alteration results from a G to T substitution at nucleotide position 1765, causing the alanine (A) at amino acid position 589 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at