7-27163607-T-C

Position:

• chr7-27163607-T-C

Variant summary

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

The NM_152739.4(HOXA9):​c.815A>G​(p.Glu272Gly) 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: not found (cov: 32)
• Consequence: HOXA9 NM_152739.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

Genes affected

HOXA9 (HGNC:5109): (homeobox A9) In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. This gene is highly similar to the abdominal-B (Abd-B) gene of Drosophila. A specific translocation event which causes a fusion between this gene and the NUP98 gene has been associated with myeloid leukemogenesis. Read-through transcription exists between this gene and the upstream homeobox A10 (HOXA10) gene.[provided by RefSeq, Mar 2011]

ENSG00000257184 (HGNC:51908):

HOXA10-HOXA9 (HGNC:):

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=0.40541515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA9	NM_152739.4	c.815A>G	p.Glu272Gly	missense_variant	2/2	ENST00000343483.7	NP_689952.1
HOXA10-HOXA9	NR_037940.1	n.941A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA9	ENST00000343483.7	c.815A>G	p.Glu272Gly	missense_variant	2/2	1	NM_152739.4	ENSP00000343619.6
ENSG00000257184	ENST00000470747.4	c.335A>G	p.Glu112Gly	missense_variant	3/3	3		ENSP00000421799.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 29, 2024

The c.815A>G (p.E272G) alteration is located in exon 2 (coding exon 2) of the HOXA9 gene. This alteration results from a A to G substitution at nucleotide position 815, causing the glutamic acid (E) at amino acid position 272 to be replaced by a glycine (G). 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.77	P;.
Vest4		0.47
MutPred		0.28		Loss of stability (P = 0.0832);.;
MVP		0.78
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.58

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: rs1783249196; hg19: chr7-27203226; COSMIC: COSV58656792; COSMIC: COSV58656792;