17-48593285-A-T

Variant names:

• chr17-48593285-A-T
• rs767917919
• NM_002147.4:c.398T>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002147.4(HOXB5):​c.398T>A​(p.Ile133Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HOXB5 NM_002147.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.80

Genes affected

HOXB5 (HGNC:5116): (homeobox B5) 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 lung and gut development. Increased expression of this gene is associated with a distinct biologic subset of acute myeloid leukemia (AML) and the occurrence of bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM) tissue. [provided by RefSeq, Jul 2008]

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3395391).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB5	NM_002147.4	c.398T>A	p.Ile133Lys	missense_variant	Exon 1 of 2	ENST00000239151.6	NP_002138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXB5	ENST00000239151.6	c.398T>A	p.Ile133Lys	missense_variant	Exon 1 of 2	1	NM_002147.4	ENSP00000239151.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250280 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135430

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 SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461110 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 726762

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: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.032
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.47
Sift	Benign	0.93	T
Sift4G	Benign	0.91	T
Polyphen		0.012	B
Vest4		0.57
MutPred		0.42		Gain of ubiquitination at I133 (P = 0.0029);
MVP		1.0
MPC		1.3
ClinPred		0.36	T
GERP RS		4.2
Varity_R		0.23
gMVP		0.43

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

Other links and lift over

dbSNP: rs767917919; hg19: chr17-46670647;