7-27165112-G-T

Variant names:

• chr7-27165112-G-T
• rs771025386
• NM_152739.4:c.346C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_152739.4(HOXA9):​c.346C>A​(p.Pro116Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000714 in 1,611,386 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (1 hom.)
• Consequence: HOXA9 NM_152739.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 0 publications found

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]

HOXA10-HOXA9 (HGNC:51908):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152739.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA9	NM_152739.4	MANE Select	c.346C>A	p.Pro116Thr	missense	Exon 1 of 2	NP_689952.1	P31269
	HOXA10-HOXA9	NM_001433944.1		c.11-145C>A		intron	N/A	NP_001420873.1	D6RAR5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA9	ENST00000343483.7	TSL:1 MANE Select	c.346C>A	p.Pro116Thr	missense	Exon 1 of 2	ENSP00000343619.6	P31269
	HOXA10-HOXA9	ENST00000470747.5	TSL:3	c.11-145C>A		intron	N/A	ENSP00000421799.3
	HOXA9	ENST00000465941.1	TSL:1	n.480-1271C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152262 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000749 AC: 18 AN: 240222 AF XY: 0.0000989

Gnomad AFR exome AF: 0.0000680

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000749

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000631 AC: 92 AN: 1459124 Hom.: 1 Cov.: 32 AF XY: 0.0000730 AC XY: 53 AN XY: 725696

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.000157 AC: 7 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000221 AC: 19 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52536

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5740

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1110940

Other (OTH) AF: 0.000133 AC: 8 AN: 60176

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00111 AC: 17 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68050

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.0000909 AC: 11

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.57
Sift	Benign	0.27	T
Sift4G	Uncertain	0.056	T
Polyphen		0.37	B
Vest4		0.62
MutPred		0.60		Gain of catalytic residue at P116 (P = 0.0372)
MVP		0.91
MPC		1.4
ClinPred		0.12	T
GERP RS		5.6
PromoterAI		-0.0047	Neutral
Varity_R		0.17
gMVP		0.28
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771025386; hg19: chr7-27204731;