chr17-48529619-C-G

Position:

• chr17-48529619-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002144.4(HOXB1):​c.834G>C​(p.Glu278Asp) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E278E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HOXB1 NM_002144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.672

Genes affected

HOXB1 (HGNC:5111): (homeobox B1) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXB genes located in a cluster on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14042836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOXB1	NM_002144.4	c.834G>C	p.Glu278Asp	missense_variant	2/2	ENST00000239174.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOXB1	ENST00000239174.7	c.834G>C	p.Glu278Asp	missense_variant	2/2	1	NM_002144.4	P1
HOXB1	ENST00000577092.1	c.*587G>C		3_prime_UTR_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.834G>C (p.E278D) alteration is located in exon 2 (coding exon 2) of the HOXB1 gene. This alteration results from a G to C substitution at nucleotide position 834, causing the glutamic acid (E) at amino acid position 278 to be replaced by an aspartic acid (D). 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	0.079
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.57	.;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.72	N;.
REVEL	Benign	0.28
Sift	Benign	0.39	T;.
Sift4G	Benign	0.38	T;.
Polyphen		0.96	P;P
Vest4		0.070
MutPred		0.15		Loss of methylation at K277 (P = 0.1354);Loss of methylation at K277 (P = 0.1354);
MVP		0.87
MPC		0.38
ClinPred		0.57	D
GERP RS		0.69
Varity_R		0.055
gMVP		0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-46606981;