17-48593604-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002147.4(HOXB5):c.79G>A(p.Gly27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (1 hom.)
• Consequence: HOXB5 NM_002147.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030691981).
• BS2: High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXB5	NM_002147.4	c.79G>A	p.Gly27Ser	missense_variant	1/2	ENST00000239151.6
HOXB-AS3	NR_033201.2	n.170+3015C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXB5	ENST00000239151.6	c.79G>A	p.Gly27Ser	missense_variant	1/2	1	NM_002147.4	P1
HOXB-AS3	ENST00000465846.6	n.78-6843C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000490 AC: 12 AN: 244734 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133762

Gnomad AFR exome AF: 0.000727

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460796 Hom.: 1 Cov.: 35 AF XY: 0.0000206 AC XY: 15 AN XY: 726712

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152266 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74452

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.0000751 AC: 9

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

Aug 30, 2022

The c.79G>A (p.G27S) alteration is located in exon 1 (coding exon 1) of the HOXB5 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the glycine (G) at amino acid position 27 to be replaced by a serine (S). 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	Benign	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Benign	0.93
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.70	N
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.18	N
REVEL	Uncertain	0.33
Sift	Benign	0.70	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.99
MPC		0.76
ClinPred		0.040	T
GERP RS		4.3
Varity_R		0.082
gMVP		0.27

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: rs752996896; hg19: chr17-46670966;