17-48726996-G-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_006361.6(HOXB13):c.649C>T(p.Arg217Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,611,558 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 (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 0 hom. )
Consequence
HOXB13
NM_006361.6 missense
NM_006361.6 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 1.67
Genes affected
HOXB13 (HGNC:5112): (homeobox B13) This gene encodes a transcription factor that belongs to the homeobox gene family. Genes of this family are highly conserved among vertebrates and essential for vertebrate embryonic development. This gene has been implicated to play a role in fetal skin development and cutaneous regeneration. In mice, a similar gene was shown to exhibit temporal and spatial colinearity in the main body axis of the embryo, but was not expressed in the secondary axes, which suggests functions in body patterning along the axis. This gene and other HOXB genes form a gene cluster at chromosome the 17q21-22 region. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a chain Homeobox protein Hox-B13 (size 283) in uniprot entity HXB13_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_006361.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HOXB13 | NM_006361.6 | c.649C>T | p.Arg217Cys | missense_variant | 2/2 | ENST00000290295.8 | NP_006352.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HOXB13 | ENST00000290295.8 | c.649C>T | p.Arg217Cys | missense_variant | 2/2 | 1 | NM_006361.6 | ENSP00000290295 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152102Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
19
AN:
152102
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000136 AC: 34AN: 249444Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 135018
GnomAD3 exomes
AF:
AC:
34
AN:
249444
Hom.:
AF XY:
AC XY:
17
AN XY:
135018
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000264 AC: 385AN: 1459456Hom.: 0 Cov.: 31 AF XY: 0.000247 AC XY: 179AN XY: 726148
GnomAD4 exome
AF:
AC:
385
AN:
1459456
Hom.:
Cov.:
31
AF XY:
AC XY:
179
AN XY:
726148
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000125 AC: 19AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74290
GnomAD4 genome
AF:
AC:
19
AN:
152102
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
74290
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
2
ALSPAC
AF:
AC:
0
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
5
ExAC
AF:
AC:
14
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 21, 2023 | In the published literature, this variant has been reported in individuals with breast cancer, prostate cancer, and unaffected controls (PMIDs: 27424772 (2016), 23064873 (2013)). The frequency of this variant in the general population, 0.00026 (34/128928 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in two prostate cancer kindreds, but was reported to not segregate with disease (PMID: 23064873); Case-control studies show no significant association with breast cancer (PMID: 27424772, 32546843); This variant is associated with the following publications: (PMID: 27424772, 28798948, 28072499, 22841674, 22236224, 34609407, 19389631, 8756292, 23064873, 32546843) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 217 of the HOXB13 protein (p.Arg217Cys). This variant is present in population databases (rs139475791, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast and prostate cancer (PMID: 23064873, 27424772, 32546843). ClinVar contains an entry for this variant (Variation ID: 483473). 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. - |
HOXB13-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2024 | The HOXB13 c.649C>T variant is predicted to result in the amino acid substitution p.Arg217Cys. This variant has been reported in two families with prostate cancer, but did not co-segregate with disease (Xu et al. 2013. PubMed ID: 23064873). It has been reported in a prostate cancer cohort study assessing HOXB13 haplotypes: however, no clinical information was provided (Karlsson et al. 2014. PubMed ID: 22841674). This variant has also been reported in two large breast cancer cohort studies and determined to confer no increased risk of female breast cancer (Liu et al. 2016. PubMed ID: 27424772; Liu et al. 2020. PubMed ID: 32546843). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/483473). 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 23, 2023 | The p.R217C variant (also known as c.649C>T), located in coding exon 2 of the HOXB13 gene, results from a C to T substitution at nucleotide position 649. The arginine at codon 217 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in two unrelated European families with familial prostate cancer; however, authors state that the variant did not co-segregate with disease in either family (Xu J et al. Hum. Genet. 2013 Jan;132:5-14). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at