17-48613284-T-G

Variant names:

• chr17-48613284-T-G
• rs369933784
• NM_024016.4:c.650A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024016.4(HOXB8):​c.650A>C​(p.Gln217Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: HOXB8 NM_024016.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.30

Genes affected

HOXB8 (HGNC:5119): (homeobox B8) 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 colorectal cancer. Mice that have had the murine ortholog of this gene knocked out exhibit an excessive pathologic grooming behavior. This behavior is similar to the behavior of humans suffering from the obsessive-compulsive spectrum disorder trichotillomania. [provided by RefSeq, Jul 2008]

HOXB7 (HGNC:5118): (homeobox B7) This gene is a member of the Antp homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded nuclear protein functions as a sequence-specific transcription factor that is involved in cell proliferation and differentiation. Increased expression of this gene is associated with some cases of melanoma and ovarian carcinoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33397937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXB8	NM_024016.4	c.650A>C	p.Gln217Pro	missense_variant	Exon 2 of 2	ENST00000239144.5	NP_076921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXB8	ENST00000239144.5	c.650A>C	p.Gln217Pro	missense_variant	Exon 2 of 2	2	NM_024016.4	ENSP00000239144.4
HOXB8	ENST00000576562.1	c.647A>C	p.Gln216Pro	missense_variant	Exon 2 of 2	2		ENSP00000460659.1
HOXB8	ENST00000498634.2	c.194A>C	p.Gln65Pro	missense_variant	Exon 1 of 2	3		ENSP00000460254.1
HOXB7	ENST00000567101.2	n.60-5189A>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152092 Hom.: 0 Cov.: 30 FAILED QC

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

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: 0.00

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.650A>C (p.Q217P) alteration is located in exon 2 (coding exon 2) of the HOXB8 gene. This alteration results from a A to C substitution at nucleotide position 650, causing the glutamine (Q) at amino acid position 217 to be replaced by a proline (P). 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	0.58
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.47
Sift	Benign	0.20	T;.
Sift4G	Benign	0.24	T;T
Polyphen		0.98	D;.
Vest4		0.45
MutPred		0.25		Gain of glycosylation at Q217 (P = 0.0483);.;
MVP		0.89
MPC		2.1
ClinPred		0.85	D
GERP RS		3.0
Varity_R		0.53
gMVP		0.75

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: rs369933784; hg19: chr17-46690646;