chr7-27165064-T-C

Position:

• chr7-27165064-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.394A>G​(p.Ile132Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXA9 NM_152739.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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=0.27777672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA9	NM_152739.4	c.394A>G	p.Ile132Val	missense_variant	1/2	ENST00000343483.7	NP_689952.1
HOXA10-HOXA9	NR_037940.1	n.617-97A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA9	ENST00000343483.7	c.394A>G	p.Ile132Val	missense_variant	1/2	1	NM_152739.4	ENSP00000343619.6
ENSG00000257184	ENST00000470747.4	c.11-97A>G		intron_variant		3		ENSP00000421799.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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 06, 2024

The c.394A>G (p.I132V) alteration is located in exon 1 (coding exon 1) of the HOXA9 gene. This alteration results from a A to G substitution at nucleotide position 394, causing the isoleucine (I) at amino acid position 132 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.33
Sift	Benign	0.40	T
Sift4G	Benign	0.41	T
Polyphen		0.39	B
Vest4		0.14
MutPred		0.54		Loss of catalytic residue at L137 (P = 0.0367);
MVP		0.89
MPC		1.1
ClinPred		0.64	D
GERP RS		5.7
Varity_R		0.12
gMVP		0.21

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: rs1357490609; hg19: chr7-27204683;