rs281865154

Positions:

• chr11-44275494-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_021926.4(ALX4):​c.631A>G​(p.Lys211Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ALX4 NM_021926.4 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 6.26

Genes affected

ALX4 (HGNC:450): (ALX homeobox 4) This gene encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones, limbs, hair, teeth, and mammary tissue. Mutations in this gene cause parietal foramina 2 (PFM2); an autosomal dominant disease characterized by deficient ossification of the parietal bones. Mutations in this gene also cause a form of frontonasal dysplasia with alopecia and hypogonadism; suggesting a role for this gene in craniofacial development, mesenchymal-epithelial communication, and hair follicle development. Deletion of a segment of chromosome 11 containing this gene, del(11)(p11p12), causes Potocki-Shaffer syndrome (PSS); a syndrome characterized by craniofacial anomalies, cognitive disability, multiple exostoses, and genital abnormalities in males. In mouse, this gene has been shown to use dual translation initiation sites located 16 codons apart. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4	c.631A>G	p.Lys211Glu	missense_variant	2/4	ENST00000652299.1	NP_068745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1	c.631A>G	p.Lys211Glu	missense_variant	2/4		NM_021926.4	ENSP00000498217.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461742 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Craniosynostosis 5, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.012	D
Sift4G	Benign	0.077	T
Polyphen		0.98	D
Vest4		0.60
MutPred		0.45		Loss of MoRF binding (P = 0.0053);
MVP		0.96
MPC		1.2
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.42
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs281865154; hg19: chr11-44297044;