dbSNP rs778919584: HOXB6:p.Glu83Asp (chr17-48597902-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018952.5(HOXB6):c.249G>T(p.Glu83Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

HOXB6
NM_018952.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.300

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.123500496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB6	NM_018952.5 link	c.249G>T	p.Glu83Asp	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.249G>T	p.Glu83Asp	missense_variant	Exon 3 of 4	1	NM_018952.5	ENSP00000225648.3		P17509-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431156

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709152

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32626

American (AMR)

AF:

0.00

AC:

AN:

41028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25578

East Asian (EAS)

AF:

0.00

AC:

AN:

37696

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096350

Other (OTH)

AF:

0.00

AC:

AN:

59080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.79

.;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.68

N;N

PhyloP100

0.30

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.46

N;N

REVEL

Benign

0.29

Sift

Benign

0.81

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.0070

B;B

Vest4

0.13

MutPred

0.23

Loss of glycosylation at S86 (P = 0.1486);Loss of glycosylation at S86 (P = 0.1486);

MVP

0.93

MPC

0.31

ClinPred

0.21

GERP RS

5.4

Varity_R

0.14

gMVP

0.38

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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rs778919584

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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