NM_005523.6:c.679G>T

Variant names:

• chr7-27184466-C-A
• rs771859968
• NM_005523.6:c.679G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005523.6(HOXA11):​c.679G>T​(p.Gly227Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,409,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G227R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HOXA11 NM_005523.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15
• Publications: 1 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]

ENSG00000293630 (HGNC:):

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

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.679G>T	p.Gly227Cys	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.679G>T	p.Gly227Cys	missense	Exon 1 of 2	ENSP00000006015.3	P31270
	HOXA11	ENST00000517402.1	TSL:1	c.586G>T	p.Gly196Cys	missense	Exon 2 of 3	ENSP00000448962.1	H0YIA6
	ENSG00000293630	ENST00000716621.1		n.382-4135C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000613 AC: 1 AN: 163074 AF XY: 0.0000113

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409052 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 696766

African (AFR) AF: 0.00 AC: 0 AN: 31658

American (AMR) AF: 0.00 AC: 0 AN: 38296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25342

East Asian (EAS) AF: 0.00 AC: 0 AN: 36504

South Asian (SAS) AF: 0.00 AC: 0 AN: 80076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4528

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085516

Other (OTH) AF: 0.00 AC: 0 AN: 58220

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000858 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.5	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.41		Loss of relative solvent accessibility (P = 0.008)
MVP		0.89
MPC		2.1
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.66
Mutation Taster		=4/96	disease causing

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: rs771859968; hg19: chr7-27224085;