17-48550642-C-T

Variant summary

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

The NM_001384749.1(HOXB3):c.988G>A(p.Glu330Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,524,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HOXB3 NM_001384749.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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]

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

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

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3153312).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXB3	NM_001384749.1	c.988G>A	p.Glu330Lys	missense_variant	5/5	ENST00000498678.6
HOXB-AS1	NR_102279.1	n.579+240C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXB3	ENST00000498678.6	c.988G>A	p.Glu330Lys	missense_variant	5/5	2	NM_001384749.1	P1
HOXB-AS1	ENST00000435312.5	n.579+240C>T		intron_variant, non_coding_transcript_variant		5
HOXB-AS3	ENST00000465846.6	n.77+696C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000339 AC: 6 AN: 177166 Hom.: 0 AF XY: 0.0000531 AC XY: 5 AN XY: 94132

Gnomad AFR exome AF: 0.0000694

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000195

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 31 AN: 1372728 Hom.: 0 Cov.: 32 AF XY: 0.0000252 AC XY: 17 AN XY: 674030

Gnomad4 AFR exome AF: 0.0000658

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000159

Gnomad4 OTH exome AF: 0.0000531

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.988G>A (p.E330K) alteration is located in exon 4 (coding exon 2) of the HOXB3 gene. This alteration results from a G to A substitution at nucleotide position 988, causing the glutamic acid (E) at amino acid position 330 to be replaced by a lysine (K). 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	0.61
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;D;D;T;.;.;D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.3	L;.;L;L;.;.;.;L
MutationTaster	Benign	0.74	D;D;D;N;N;N;N;N;N;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D
Sift4G	Benign	0.074	T;T;T;T;T;T;T;T
Polyphen		0.84	P;.;P;P;.;.;.;P
Vest4		0.26
MutPred		0.27		Gain of methylation at E330 (P = 0.0061);.;Gain of methylation at E330 (P = 0.0061);Gain of methylation at E330 (P = 0.0061);.;.;.;Gain of methylation at E330 (P = 0.0061);
MVP		0.75
MPC		0.69
ClinPred		0.37	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.42
gMVP		0.59

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: rs780476140; hg19: chr17-46628004;