NM_006361.6:c.649C>G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_006361.6(HOXB13):āc.649C>Gā(p.Arg217Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,459,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_006361.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249444Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135018
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1459456Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7AN XY: 726148
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 217 of the HOXB13 protein (p.Arg217Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HOXB13-related conditions. ClinVar contains an entry for this variant (Variation ID: 483512). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HOXB13 protein function with a positive predictive value of 80%. 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. -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19389631, 8756292) -
HOXB13-related disorder Uncertain:1
The HOXB13 c.649C>G variant is predicted to result in the amino acid substitution p.Arg217Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and it is reported in ClinVar as a variant of uncertain clinical significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/483512/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R217G variant (also known as c.649C>G), located in coding exon 2 of the HOXB13 gene, results from a C to G substitution at nucleotide position 649. The arginine at codon 217 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at