chr17-48550642-C-T

Variant names:

• chr17-48550642-C-T
• rs780476140
• NM_001384749.1:c.988G>A

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3153312).
• BS2: High AC in GnomAdExome4 at 31 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXB3	NM_001384749.1	MANE Select	c.988G>A	p.Glu330Lys	missense	Exon 5 of 5	NP_001371678.1	P14651-1
	HOXB3	NM_001384747.1		c.988G>A	p.Glu330Lys	missense	Exon 3 of 3	NP_001371676.1	P14651-1
	HOXB3	NM_002146.4		c.988G>A	p.Glu330Lys	missense	Exon 4 of 4	NP_002137.4	B3KNJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXB3	ENST00000498678.6	TSL:2 MANE Select	c.988G>A	p.Glu330Lys	missense	Exon 5 of 5	ENSP00000420595.1	P14651-1
	HOXB3	ENST00000311626.8	TSL:1	c.988G>A	p.Glu330Lys	missense	Exon 4 of 4	ENSP00000308252.4	P14651-1
	HOXB3	ENST00000470495.1	TSL:1	c.988G>A	p.Glu330Lys	missense	Exon 2 of 2	ENSP00000417207.1	P14651-1

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

GnomAD2 exomes AF: 0.0000339 AC: 6 AN: 177166 AF XY: 0.0000531

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 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

African (AFR) AF: 0.0000658 AC: 2 AN: 30382

American (AMR) AF: 0.00 AC: 0 AN: 30604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20312

East Asian (EAS) AF: 0.00 AC: 0 AN: 39004

South Asian (SAS) AF: 0.000126 AC: 9 AN: 71584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 0.0000159 AC: 17 AN: 1071488

Other (OTH) AF: 0.0000531 AC: 3 AN: 56472

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

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.074	T
Polyphen		0.84	P
Vest4		0.26
MutPred		0.27		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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs780476140; hg19: chr17-46628004;