rs12419361

Positions:

• chr11-44267521-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021926.4(ALX4):​c.879C>T​(p.Leu293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,974 control chromosomes in the GnomAD database, including 9,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (768 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8802 hom.)
• Consequence: ALX4 NM_021926.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.303

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 11-44267521-G-A is Benign according to our data. Variant chr11-44267521-G-A is described in ClinVar as [Benign]. Clinvar id is 304702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44267521-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.303 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4	c.879C>T	p.Leu293=	synonymous_variant	3/4	ENST00000652299.1	NP_068745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1	c.879C>T	p.Leu293=	synonymous_variant	3/4		NM_021926.4	ENSP00000498217	P1

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14830 AN: 152076 Hom.: 770 Cov.: 32

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0994

GnomAD3 exomes AF: 0.110 AC: 27768 AN: 251342 Hom.: 1629 AF XY: 0.112 AC XY: 15253 AN XY: 135854

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.0911

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.107 AC: 155805 AN: 1461778 Hom.: 8802 Cov.: 32 AF XY: 0.107 AC XY: 78140 AN XY: 727186

Gnomad4 AFR exome AF: 0.0538

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0974 AC: 14823 AN: 152196 Hom.: 768 Cov.: 32 AF XY: 0.101 AC XY: 7530 AN XY: 74398

Gnomad4 AFR AF: 0.0560

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0993

Alfa AF: 0.105 Hom.: 1113

Bravo AF: 0.0893

Asia WGS AF: 0.145 AC: 506 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	-0.59
CADD	Benign	5.8
DANN	Benign	0.79

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: rs12419361; hg19: chr11-44289071;