rs140076136
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_001130438.3(SPTAN1):c.959G>A(p.Arg320His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,068 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001130438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251308Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135818
GnomAD4 exome AF: 0.000153 AC: 223AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.000133 AC XY: 97AN XY: 727246
GnomAD4 genome AF: 0.000112 AC: 17AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2
p.Arg320His (CGC>CAC): c.959 G>A in exon 8 of the SPTAN1 gene (NM_001130438.1) The Arg320His missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project did not identify Arg320His in approximately 5000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Arg320His alters a position that is highly conserved in the alpha-II spectrin protein, and multiple in silico algorithms predict this variant may be damaging to protein structure/function. However, previously reported pathogenic missense mutations in SPTAN1 are located within the last four spectrin repeats that are essential for dimerization (Saitsu et al., 2010), and the Arg320 residue is outside this region. Additionally, the amino acid substitution is conservative, as Arginine and Histidine are both positively charged amino acids. Therefore, based on the currently available information it is unclear whether Arg320His is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -
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Early infantile epileptic encephalopathy with suppression bursts Benign:1
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Developmental and epileptic encephalopathy, 5 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at