7-27163674-C-G

Variant names:

• chr7-27163674-C-G
• rs1451206928
• NM_152739.4:c.748G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152739.4(HOXA9):​c.748G>C​(p.Val250Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V250F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOXA9 NM_152739.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA9	NM_152739.4	c.748G>C	p.Val250Leu	missense_variant	Exon 2 of 2	ENST00000343483.7	NP_689952.1
HOXA10-HOXA9	NR_037940.1	n.874G>C		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA9	ENST00000343483.7	c.748G>C	p.Val250Leu	missense_variant	Exon 2 of 2	1	NM_152739.4	ENSP00000343619.6
ENSG00000257184	ENST00000470747.4	c.268G>C	p.Val90Leu	missense_variant	Exon 3 of 3	3		ENSP00000421799.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.73		Gain of loop (P = 0.1069);.;
MVP		0.94
MPC		1.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.99

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: rs1451206928; hg19: chr7-27203293;