17-48728472-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006361.6(HOXB13):​c.122C>A​(p.Thr41Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T41M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HOXB13
NM_006361.6 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.79

Publications

6 publications found
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]
HOXB13 Gene-Disease associations (from GenCC):
  • prostate cancer
    Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
  • prostate cancer, hereditary, 9
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19807017).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXB13NM_006361.6 linkc.122C>A p.Thr41Lys missense_variant Exon 1 of 2 ENST00000290295.8 NP_006352.2 Q92826Q4KR72

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXB13ENST00000290295.8 linkc.122C>A p.Thr41Lys missense_variant Exon 1 of 2 1 NM_006361.6 ENSP00000290295.8 Q92826

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000401
AC:
1
AN:
249102
AF XY:
0.00000740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460878
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726748
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44670
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86182
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52840
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5746
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111826
Other (OTH)
AF:
0.00
AC:
0
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Prostate cancer, hereditary, 1 Uncertain:1
-
Laboratory of Virology, Microbiology, Quality and Medical Biotechnologies, Faculty of Sciences and Techniques - Mohammedia, Hassan II University of Casablanca
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Uncertain:1
Oct 28, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine with lysine at codon 41 of the HOXB13 protein (p.Thr41Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HOXB13-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.064
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.13
T
Eigen
Benign
-0.036
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.41
T
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.20
T
MetaSVM
Uncertain
-0.086
T
MutationAssessor
Benign
1.4
L
PhyloP100
3.8
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.41
N
REVEL
Benign
0.29
Sift
Benign
0.046
D
Sift4G
Benign
0.38
T
Polyphen
0.080
B
Vest4
0.22
MutPred
0.29
Gain of ubiquitination at T41 (P = 0.0075);
MVP
0.92
MPC
0.57
ClinPred
0.51
D
GERP RS
4.9
PromoterAI
-0.032
Neutral
Varity_R
0.26
gMVP
0.32

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

Other links and lift over

dbSNP: rs199799743; hg19: chr17-46805834; API