7-27184501-C-T

Variant names:

• chr7-27184501-C-T
• rs764993725
• NM_005523.6:c.644G>A

Variant summary

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

The NM_005523.6(HOXA11):​c.644G>A​(p.Arg215His) variant causes a missense change. The variant allele was found at a frequency of 0.000000724 in 1,381,488 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R215L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: HOXA11 NM_005523.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• 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]

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.644G>A	p.Arg215His	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.644G>A	p.Arg215His	missense	Exon 1 of 2	ENSP00000006015.3	P31270
	HOXA11	ENST00000517402.1	TSL:1	c.551G>A	p.Arg184His	missense	Exon 2 of 3	ENSP00000448962.1	H0YIA6
	ENSG00000293630	ENST00000716621.1		n.382-4100C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681770

African (AFR) AF: 0.00 AC: 0 AN: 29768

American (AMR) AF: 0.00 AC: 0 AN: 34542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24766

East Asian (EAS) AF: 0.00 AC: 0 AN: 33590

South Asian (SAS) AF: 0.00 AC: 0 AN: 77874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4376

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071646

Other (OTH) AF: 0.00 AC: 0 AN: 57168

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.35
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.97	D
Vest4		0.22
MutPred		0.32		Loss of solvent accessibility (P = 0.0635)
MVP		0.80
MPC		1.4
ClinPred		0.43	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.51
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: rs764993725; hg19: chr7-27224120;