Genetic Variant HOXB3:p.Gly338Arg (chr17-48550618-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_001384749.1(HOXB3):c.1012G>C(p.Gly338Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,521,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HOXB3
NM_001384749.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67

Publications

3 publications found

Variant links:

Genes affected

HOXB3 (HGNC:5114): (homeobox B3) 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 a distinct biologic subset of acute myeloid leukemia (AML). [provided by RefSeq, Jul 2008]

HOXB3 links:

HOXB-AS1 (HGNC:43744): (HOXB cluster antisense RNA 1)

HOXB-AS1 links:

HOXB-AS3 (HGNC:40283): (HOXB cluster antisense RNA 3)

HOXB-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

BS2

High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384749.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOXB3	NM_001384749.1	MANE Select	c.1012G>C	p.Gly338Arg	missense	Exon 5 of 5	NP_001371678.1	P14651-1
HOXB3	NM_001384747.1		c.1012G>C	p.Gly338Arg	missense	Exon 3 of 3	NP_001371676.1	P14651-1
HOXB3	NM_002146.4		c.1012G>C	p.Gly338Arg	missense	Exon 4 of 4	NP_002137.4	B3KNJ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOXB3	ENST00000498678.6	TSL:2 MANE Select	c.1012G>C	p.Gly338Arg	missense	Exon 5 of 5	ENSP00000420595.1	P14651-1
HOXB3	ENST00000311626.8	TSL:1	c.1012G>C	p.Gly338Arg	missense	Exon 4 of 4	ENSP00000308252.4	P14651-1
HOXB3	ENST00000470495.1	TSL:1	c.1012G>C	p.Gly338Arg	missense	Exon 2 of 2	ENSP00000417207.1	P14651-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000115

AC:

AN:

173544

AF XY:

0.0000108

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:

0.0000233

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1369048

Hom.:

Cov.:

AF XY:

0.00000446

AC XY:

AN XY:

672370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30246

American (AMR)

AF:

0.00

AC:

AN:

29694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20264

East Asian (EAS)

AF:

0.00

AC:

AN:

38988

South Asian (SAS)

AF:

0.00

AC:

AN:

71478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5310

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

1071058

Other (OTH)

AF:

0.00

AC:

AN:

56390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.2

PhyloP100

2.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.60

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.66

MutPred

0.19

Gain of catalytic residue at G338 (P = 0.0387)

MVP

0.98

MPC

1.4

ClinPred

0.92

GERP RS

3.8

Varity_R

0.51

gMVP

0.55

Mutation Taster

=43/57

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over