chr7-27165166-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152739.4(HOXA9):​c.292G>C​(p.Val98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,596,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

HOXA9
NM_152739.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.501
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11126411).
BS2
High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXA9NM_152739.4 linkc.292G>C p.Val98Leu missense_variant Exon 1 of 2 ENST00000343483.7 NP_689952.1 P31269
HOXA10-HOXA9NR_037940.1 linkn.617-199G>C intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXA9ENST00000343483.7 linkc.292G>C p.Val98Leu missense_variant Exon 1 of 2 1 NM_152739.4 ENSP00000343619.6 P31269
ENSG00000257184ENST00000470747.4 linkc.11-199G>C intron_variant Intron 1 of 2 3 ENSP00000421799.3 D6RAR5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
GnomAD3 exomes
AF:
0.0000133
AC:
3
AN:
225118
Hom.:
0
AF XY:
0.0000161
AC XY:
2
AN XY:
123998
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000299
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000242
AC:
35
AN:
1444836
Hom.:
0
Cov.:
32
AF XY:
0.0000112
AC XY:
8
AN XY:
717316
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000317
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152140
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Alfa
AF:
0.0000509
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000842
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.292G>C (p.V98L) alteration is located in exon 1 (coding exon 1) of the HOXA9 gene. This alteration results from a G to C substitution at nucleotide position 292, causing the valine (V) at amino acid position 98 to be replaced by a leucine (L). 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
0.085
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
18
DANN
Benign
0.89
DEOGEN2
Benign
0.17
T;.
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.50
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.64
T;T
M_CAP
Benign
0.080
D
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
0.69
N;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.38
N;N
REVEL
Benign
0.26
Sift
Benign
0.94
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;.
Vest4
0.13
MutPred
0.52
Loss of catalytic residue at V98 (P = 0.0556);Loss of catalytic residue at V98 (P = 0.0556);
MVP
0.80
MPC
0.42
ClinPred
0.030
T
GERP RS
2.4
Varity_R
0.042
gMVP
0.19

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763826633; hg19: chr7-27204785; API