X-137566710-G-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_003413.4(ZIC3):āc.19G>Cā(p.Gly7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,085,516 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. 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_003413.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 25
GnomAD3 exomes AF: 0.00000652 AC: 1AN: 153469Hom.: 0 AF XY: 0.0000209 AC XY: 1AN XY: 47917
GnomAD4 exome AF: 0.0000157 AC: 17AN: 1085516Hom.: 0 Cov.: 32 AF XY: 0.0000282 AC XY: 10AN XY: 354398
GnomAD4 genome Cov.: 25
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The Gly7Arg variant in the ZIC3 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Gly7Arg results in a non-conservative amino acid substitution of a non-polar Glycine residue with a positively charged Arginine residue at a position that is conserved across species. In silico analysis predicts Gly7Arg is probably damaging to the protein structure/function. A variant affecting a nearby residue (Gly17Cys) has been reported in HGMD in association with a cardiac malformation (Stenson P et al., 2009), further supporting the functional importance of this region of the protein. Furthermore, the Gly7Arg variant was not observed in approximately 5,300 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. In summary, while Gly7Arg is a good candidate for a pathogenic variant, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The pathogenic role for this variant would be further supported if it occurred de novo in this individual or if it co-segregates with the disease phenotype in this family. -
Heterotaxy, visceral, 1, X-linked Uncertain:1
This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 7 of the ZIC3 protein (p.Gly7Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has not been reported in the literature in individuals with ZIC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 418553). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at