chr11-44264626-G-A

Position:

• chr11-44264626-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021926.4(ALX4):​c.*228C>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 0.248 in 589,360 control chromosomes in the GnomAD database, including 19,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4422 hom., cov: 34)
  • Exomes 𝑓: 0.25 (14783 hom.)
• Consequence: ALX4 NM_021926.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.09

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 11-44264626-G-A is Benign according to our data. Variant chr11-44264626-G-A is described in ClinVar as [Benign]. Clinvar id is 304694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4	c.*228C>T		3_prime_UTR_variant	4/4	ENST00000652299.1	NP_068745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1	c.*228C>T		3_prime_UTR_variant	4/4		NM_021926.4	ENSP00000498217	P1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35682 AN: 152128 Hom.: 4419 Cov.: 34

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.252 AC: 110200 AN: 437114 Hom.: 14783 Cov.: 4 AF XY: 0.251 AC XY: 57283 AN XY: 228086

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.239

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.234 AC: 35698 AN: 152246 Hom.: 4422 Cov.: 34 AF XY: 0.231 AC XY: 17198 AN XY: 74446

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.250

Alfa AF: 0.248 Hom.: 634

Bravo AF: 0.233

Asia WGS AF: 0.190 AC: 660 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Parietal foramina 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.76
CADD	Benign	0.41
DANN	Benign	0.84

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: rs4755798; hg19: chr11-44286176;