7-27182857-A-C

Position:

• chr7-27182857-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_005523.6(HOXA11):​c.881T>G​(p.Met294Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXA11 NM_005523.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 7-27182857-A-C is Pathogenic according to our data. Variant chr7-27182857-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2203766.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA11	NM_005523.6	c.881T>G	p.Met294Arg	missense_variant	2/2	ENST00000006015.4	NP_005514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA11	ENST00000006015.4	c.881T>G	p.Met294Arg	missense_variant	2/2	1	NM_005523.6	ENSP00000006015.3
HOXA11	ENST00000517402.1	c.788T>G	p.Met263Arg	missense_variant	3/3	1		ENSP00000448962.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mesomelic dysplasia with urogenital abnormalities Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Medical Genetics, Gazi University

Jan 23, 2023

This variant has not been reported in the literature, variant databases (ClinVar and LOVD), or population data (GnomAD). Other genes/loci, which were linked to mesomelic dysplasia and/or urogenital anomalies, were also screened by array CGH, and WES analyses, and any reportable variants were not detected. Also, there were not any additional rare variants in HOXA11 and its paralogs, HOXC11, and HOXD11 genes. The amino acid residue p.Met294 of HOXA11, in the homeodomain region, was conserved in the vertebrates with the surrounding sequence by multisequence alignment. This variant was predicted to be deleterious according to in silico tools (MutationTaster, SIFT, and Revel). Additionally, the mutant protein was estimated to interact with the wild-type protein by docking analysis. The ΔΔG results of the in silico predictions of DNA–mutant protein interaction were -2.04, 0.99, and 0.128412 kcal/mol according to mCSM, PremPDI, and SAMPDI, respectively. Finally, the variant detected in HOXA11 was de novo in the patient with healthy parents indicating that this variant could be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.63		Gain of methylation at K295 (P = 0.0223);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-27222476;