chr7-27184591-C-T

Variant names:

• chr7-27184591-C-T
• NM_005523.6:c.554G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005523.6(HOXA11):​c.554G>A​(p.Gly185Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HOXA11 NM_005523.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33681738).

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.554G>A	p.Gly185Asp	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.554G>A	p.Gly185Asp	missense	Exon 1 of 2	ENSP00000006015.3	P31270
	HOXA11	ENST00000517402.1	TSL:1	c.461G>A	p.Gly154Asp	missense	Exon 2 of 3	ENSP00000448962.1	H0YIA6
	HOXA11-AS	ENST00000520360.6	TSL:5	n.85C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1343714 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 662674

African (AFR) AF: 0.00 AC: 0 AN: 27330

American (AMR) AF: 0.00 AC: 0 AN: 27858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23222

East Asian (EAS) AF: 0.00 AC: 0 AN: 31320

South Asian (SAS) AF: 0.00 AC: 0 AN: 72652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054484

Other (OTH) AF: 0.00 AC: 0 AN: 55344

GnomAD4 genome Cov.: 32

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	0.15
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.35
Sift	Benign	0.48	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.27		Loss of helix (P = 0.1299)
MVP		0.77
MPC		1.2
ClinPred		0.24	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.45
Mutation Taster		=94/6	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

hg19: chr7-27224210;