chr17-48614289-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024016.4(HOXB8):​c.416G>A​(p.Arg139His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,361,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

HOXB8
NM_024016.4 missense

Scores

3
13
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
HOXB8 (HGNC:5119): (homeobox B8) This gene is a member of the Antp homeobox family and encodes a nuclear protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development. Increased expression of this gene is associated with colorectal cancer. Mice that have had the murine ortholog of this gene knocked out exhibit an excessive pathologic grooming behavior. This behavior is similar to the behavior of humans suffering from the obsessive-compulsive spectrum disorder trichotillomania. [provided by RefSeq, Jul 2008]
HOXB7 (HGNC:5118): (homeobox B7) This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded nuclear protein functions as a sequence-specific transcription factor that is involved in cell proliferation and differentiation. Increased expression of this gene is associated with some cases of melanoma and ovarian carcinoma. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXB8NM_024016.4 linkc.416G>A p.Arg139His missense_variant Exon 1 of 2 ENST00000239144.5 NP_076921.1 P17481Q8N8T3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXB8ENST00000239144.5 linkc.416G>A p.Arg139His missense_variant Exon 1 of 2 2 NM_024016.4 ENSP00000239144.4 P17481
HOXB8ENST00000576562.1 linkc.416G>A p.Arg139His missense_variant Exon 1 of 2 2 ENSP00000460659.1 I3L3R1
HOXB7ENST00000567101.2 linkn.60-6194G>A intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000294
AC:
4
AN:
1361564
Hom.:
0
Cov.:
38
AF XY:
0.00000299
AC XY:
2
AN XY:
669384
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000373
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.416G>A (p.R139H) alteration is located in exon 1 (coding exon 1) of the HOXB8 gene. This alteration results from a G to A substitution at nucleotide position 416, causing the arginine (R) at amino acid position 139 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Benign
-0.028
T
BayesDel_noAF
Benign
-0.28
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.43
T;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.66
D;D
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-3.8
D;.
REVEL
Uncertain
0.38
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;.
Vest4
0.62
MutPred
0.40
Gain of catalytic residue at R139 (P = 0.0067);Gain of catalytic residue at R139 (P = 0.0067);
MVP
0.82
MPC
2.3
ClinPred
0.99
D
GERP RS
2.6
Varity_R
0.56
gMVP
0.65

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: rs1597890727; hg19: chr17-46691651; API