rs199799743

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006361.6(HOXB13):​c.122C>T​(p.Thr41Met) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,613,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T41K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

HOXB13
NM_006361.6 missense

Scores

8
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

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: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.038894176).
BP6
Variant 17-48728472-G-A is Benign according to our data. Variant chr17-48728472-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 483475.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXB13NM_006361.6 linkc.122C>T p.Thr41Met 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>T p.Thr41Met missense_variant Exon 1 of 2 1 NM_006361.6 ENSP00000290295.8 Q92826

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000120
AC:
30
AN:
249102
AF XY:
0.000104
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00158
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.000170
AC:
248
AN:
1460878
Hom.:
1
Cov.:
33
AF XY:
0.000166
AC XY:
121
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:
0.00612
AC:
243
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
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:
0.0000663
AC:
4
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
22
43
65
86
108
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000656
AC:
10
AN:
152342
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74492
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41596
American (AMR)
AF:
0.00
AC:
0
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00193
AC:
10
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0276
Hom.:
327
Bravo
AF:
0.0000453
ExAC
AF:
0.0000989
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Aug 07, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in prostate cancer cases and unaffected controls (Momozawa et al., 2019); This variant is associated with the following publications: (PMID: 28272408, 11857506, 31214711) -

Sep 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

HOXB13: BS1 -

Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Prostate cancer, hereditary, 9 Uncertain:1
Jul 05, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Sep 09, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.T41M variant (also known as c.122C>T), located in coding exon 1 of the HOXB13 gene, results from a C to T substitution at nucleotide position 122. The threonine at codon 41 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Benign:1
Jul 07, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.56
T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.039
T
MetaSVM
Uncertain
0.32
D
MutationAssessor
Benign
1.4
L
PhyloP100
3.8
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.58
N
REVEL
Uncertain
0.32
Sift
Uncertain
0.022
D
Sift4G
Benign
0.30
T
Polyphen
0.77
P
Vest4
0.10
MVP
0.93
MPC
0.79
ClinPred
0.11
T
GERP RS
4.9
PromoterAI
-0.040
Neutral
Varity_R
0.13
gMVP
0.17
Mutation Taster
=71/29
polymorphism

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; COSMIC: COSV51705732; COSMIC: COSV51705732; API