11-44261688-G-A

Position:

• chr11-44261688-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021926.4(ALX4):​c.*3166C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,142 control chromosomes in the GnomAD database, including 5,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (5567 hom., cov: 32)
  • Exomes 𝑓: 0.27 (1 hom.)
• Consequence: ALX4 NM_021926.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.176

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-44261688-G-A is Benign according to our data. Variant chr11-44261688-G-A is described in ClinVar as [Benign]. Clinvar id is 304621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX4	NM_021926.4	c.*3166C>T		3_prime_UTR_variant	4/4	ENST00000652299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX4	ENST00000652299.1	c.*3166C>T		3_prime_UTR_variant	4/4		NM_021926.4	P1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36829 AN: 151994 Hom.: 5549 Cov.: 32

Gnomad AFR AF: 0.0895

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.267 AC: 8 AN: 30 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 5 AN XY: 20

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.350

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.242 AC: 36865 AN: 152112 Hom.: 5567 Cov.: 32 AF XY: 0.250 AC XY: 18578 AN XY: 74348

Gnomad4 AFR AF: 0.0894

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.404

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.268

Alfa AF: 0.238 Hom.: 783

Bravo AF: 0.243

Asia WGS AF: 0.428 AC: 1485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parietal foramina 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.72

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: rs7116335; hg19: chr11-44283238;