NM_005523.6:c.532G>A

Variant names:

• chr7-27184613-C-T
• rs908837065
• NM_005523.6:c.532G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005523.6(HOXA11):​c.532G>A​(p.Ala178Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000329 in 1,521,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: HOXA11 NM_005523.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

Genes affected

HOXA11 (HGNC:5101): (homeobox A11) 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 involved in the regulation of uterine development and is required for female fertility. Mutations in this gene can cause radio-ulnar synostosis with amegakaryocytic thrombocytopenia. [provided by RefSeq, Jul 2008]

HOXA11-AS (HGNC:24957): (HOXA11 antisense RNA) This gene produces a long non-coding RNA in antisense to transcription of the homeobox A11 gene. This transcript may associate with chromatin factors such as Polycomb repressive complex and act as a sponge for microRNAs, thereby participating in the regulation of expression of target genes. High levels of this transcript may be associated with tumor progression. [provided by RefSeq, Dec 2017]

ENSG00000293630 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21468988).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005523.6. 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
	HOXA11	NM_005523.6	MANE Select	c.532G>A	p.Ala178Thr	missense	Exon 1 of 2	NP_005514.1	P31270

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA11	ENST00000006015.4	TSL:1 MANE Select	c.532G>A	p.Ala178Thr	missense	Exon 1 of 2	ENSP00000006015.3	P31270
	HOXA11	ENST00000517402.1	TSL:1	c.439G>A	p.Ala147Thr	missense	Exon 2 of 3	ENSP00000448962.1	H0YIA6
	HOXA11-AS	ENST00000520360.6	TSL:5	n.107C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1369318 Hom.: 0 Cov.: 32 AF XY: 0.00000296 AC XY: 2 AN XY: 676142

African (AFR) AF: 0.00 AC: 0 AN: 28438

American (AMR) AF: 0.00 AC: 0 AN: 31772

Ashkenazi Jewish (ASJ) AF: 0.0000416 AC: 1 AN: 24016

East Asian (EAS) AF: 0.00 AC: 0 AN: 32322

South Asian (SAS) AF: 0.00 AC: 0 AN: 75832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4720

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1068118

Other (OTH) AF: 0.00 AC: 0 AN: 56432

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

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	0.074
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.20
Sift	Benign	0.59	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.26		Gain of glycosylation at A178 (P = 0.0017)
MVP		0.60
MPC		0.94
ClinPred		0.043	T
GERP RS		2.0
Varity_R		0.077
gMVP		0.49
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs908837065; hg19: chr7-27224232;