Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1PP2BP4_StrongBP6_ModerateBS1BS2
The NM_001130004.2(ACTN1):c.2668A>T(p.Thr890Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,612,820 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
ACTN1 (HGNC:163): (actinin alpha 1) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
In a modified_residue Phosphoserine (size 0) in uniprot entity ACTN1_HUMAN
PP2
Missense variant in the ACTN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 3.3621 (above the threshold of 3.09). Trascript score misZ: 5.1933 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.
BP4
Computational evidence support a benign effect (MetaRNN=0.0036654174).
BP6
Variant 14-68874936-T-A is Benign according to our data. Variant chr14-68874936-T-A is described in ClinVar as [Benign]. Clinvar id is 2014611.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0113 (1715/152214) while in subpopulation AMR AF= 0.0188 (288/15294). AF 95% confidence interval is 0.017. There are 19 homozygotes in gnomad4. There are 799 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.