chr17-48550618-C-T

Variant names:

• chr17-48550618-C-T
• rs369908227
• NM_001384749.1:c.1012G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001384749.1(HOXB3):​c.1012G>A​(p.Gly338Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HOXB3 NM_001384749.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

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.1012G>A	p.Gly338Arg	missense	Exon 5 of 5	NP_001371678.1	P14651-1
	HOXB3	NM_001384747.1		c.1012G>A	p.Gly338Arg	missense	Exon 3 of 3	NP_001371676.1	P14651-1
	HOXB3	NM_002146.4		c.1012G>A	p.Gly338Arg	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.1012G>A	p.Gly338Arg	missense	Exon 5 of 5	ENSP00000420595.1	P14651-1
	HOXB3	ENST00000311626.8	TSL:1	c.1012G>A	p.Gly338Arg	missense	Exon 4 of 4	ENSP00000308252.4	P14651-1
	HOXB3	ENST00000470495.1	TSL:1	c.1012G>A	p.Gly338Arg	missense	Exon 2 of 2	ENSP00000417207.1	P14651-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1369048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 672370

African (AFR) AF: 0.00 AC: 0 AN: 30246

American (AMR) AF: 0.00 AC: 0 AN: 29694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20264

East Asian (EAS) AF: 0.00 AC: 0 AN: 38988

South Asian (SAS) AF: 0.00 AC: 0 AN: 71478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071058

Other (OTH) AF: 0.00 AC: 0 AN: 56390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.59
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.19		Gain of catalytic residue at G338 (P = 0.0387)
MVP		0.97
MPC		1.4
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.51
gMVP		0.55
Mutation Taster		=43/57	disease causing

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: rs369908227; hg19: chr17-46627980;