rs775613793

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006361.6(HOXB13):c.653A>G(p.Lys218Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,459,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K218N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

HOXB13
NM_006361.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.27

Publications

1 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)

HOXB13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB13	NM_006361.6 link	c.653A>G	p.Lys218Arg	missense_variant	Exon 2 of 2	ENST00000290295.8	NP_006352.2	Q92826Q4KR72

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXB13	ENST00000290295.8 link	c.653A>G	p.Lys218Arg	missense_variant	Exon 2 of 2	1	NM_006361.6	ENSP00000290295.8		Q92826

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000440

AC:

AN:

249850

AF XY:

0.0000592

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:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1459854

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 218 of the HOXB13 protein (p.Lys218Arg). This variant is present in population databases (rs775613793, gnomAD 0.01%). 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: 483497). 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 not expected to disrupt HOXB13 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K218R variant (also known as c.653A>G), located in coding exon 2 of the HOXB13 gene, results from an A to G substitution at nucleotide position 653. The lysine at codon 218 is replaced by arginine, an amino acid with highly similar properties. In one study, that used in silico tools, this variant was predicted to be highly deleterious and damaging to the HOXB13 homeobox protein structure (Chandrasekaran G et al. Chem Biol Drug Des. 2017 Jan;[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.31

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.62

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

0.89

PhyloP100

6.3

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.044

Polyphen

1.0

Vest4

0.46

MutPred

0.48

Loss of methylation at K218 (P = 0.0188);

MVP

0.95

MPC

1.1

ClinPred

0.67

GERP RS

5.3

Varity_R

0.89

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over