Genetic Variant HOXB6:p.Pro98Ala (chr17-48597859-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018952.5(HOXB6):c.292C>G(p.Pro98Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,443,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P98S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

HOXB6
NM_018952.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

Publications

0 publications found

Variant links:

Genes affected

HOXB6 (HGNC:5117): (homeobox B6) 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 protein functions as a sequence-specific transcription factor that is involved in development, including that of lung and skin, and has been localized to both the nucleus and cytoplasm. Altered expression of this gene or a change in the subcellular localization of its protein is associated with some cases of acute myeloid leukemia and colorectal cancer. [provided by RefSeq, Jul 2008]

HOXB6 links:

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

HOXB-AS3 links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13412952).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB6	NM_018952.5 link	c.292C>G	p.Pro98Ala	missense_variant	Exon 3 of 4	ENST00000225648.4	NP_061825.2	P17509-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXB6	ENST00000225648.4 link	c.292C>G	p.Pro98Ala	missense_variant	Exon 3 of 4	1	NM_018952.5	ENSP00000225648.3		P17509-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000925

AC:

AN:

216284

AF XY:

0.0000169

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:

0.0000214

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000762

AC:

AN:

1443866

Hom.:

Cov.:

AF XY:

0.00000977

AC XY:

AN XY:

716368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32952

American (AMR)

AF:

0.00

AC:

AN:

43140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

38556

South Asian (SAS)

AF:

0.00

AC:

AN:

84140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000998

AC:

AN:

1102560

Other (OTH)

AF:

0.00

AC:

AN:

59512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.59

.;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.23

N;N

PhyloP100

1.4

PrimateAI

Benign

0.45

PROVEAN

Benign

0.50

N;N

REVEL

Benign

0.20

Sift

Benign

0.75

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.022

B;B

Vest4

0.15

MutPred

0.26

Loss of glycosylation at P98 (P = 0.0464);Loss of glycosylation at P98 (P = 0.0464);

MVP

0.84

MPC

0.33

ClinPred

0.017

GERP RS

2.3

Varity_R

0.027

gMVP

0.30

Mutation Taster

=87/13

polymorphism

(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

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17-48597859-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over