17-48726996-G-A

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

Scores

15
3
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.67
Variant links:
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
HOXB13NM_006361.6 linkuse as main transcriptc.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
HOXB13ENST00000290295.8 linkuse as main transcriptc.649C>T p.Arg217Cys missense_variant 2/21 NM_006361.6 ENSP00000290295 P1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000136
AC:
34
AN:
249444
Hom.:
0
AF XY:
0.000126
AC XY:
17
AN XY:
135018
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000282
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000264
AC:
385
AN:
1459456
Hom.:
0
Cov.:
31
AF XY:
0.000247
AC XY:
179
AN XY:
726148
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000392
Gnomad4 NFE exome
AF:
0.000332
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000229
Hom.:
0
Bravo
AF:
0.000155
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000273
EpiControl
AF:
0.000119

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 submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 21, 2023In 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 submitterclinical testingGeneDxMar 03, 2024In 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This 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 providedclinical testingPreventionGenetics, part of Exact SciencesJun 21, 2024The 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 submitterclinical testingAmbry GeneticsJul 23, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-6.8
D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.77
MVP
0.98
MPC
1.5
ClinPred
0.96
D
GERP RS
5.3
Varity_R
0.87
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139475791; hg19: chr17-46804358; API