11-44275396-C-T

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.729G>A(p.Ala243=) 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 1,614,110 control chromosomes in the GnomAD database, including 10,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (811 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9232 hom.)
• Consequence: ALX4 NM_021926.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.84

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=-0.77).
• BP6: Variant 11-44275396-C-T is Benign according to our data. Variant chr11-44275396-C-T is described in ClinVar as [Benign]. Clinvar id is 304704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44275396-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX4	NM_021926.4	c.729G>A	p.Ala243=	synonymous_variant	2/4	ENST00000652299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX4	ENST00000652299.1	c.729G>A	p.Ala243=	synonymous_variant	2/4		NM_021926.4	P1

Frequencies

GnomAD3 genomes AF: 0.0993 AC: 15106 AN: 152120 Hom.: 810 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.0899 AC: 22601 AN: 251386 Hom.: 1208 AF XY: 0.0902 AC XY: 12250 AN XY: 135876

Gnomad AFR exome AF: 0.0751

Gnomad AMR exome AF: 0.0669

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.0358

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.107 AC: 155880 AN: 1461872 Hom.: 9232 Cov.: 35 AF XY: 0.105 AC XY: 76393 AN XY: 727236

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.0713

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0365

Gnomad4 FIN exome AF: 0.0995

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0993 AC: 15110 AN: 152238 Hom.: 811 Cov.: 33 AF XY: 0.0960 AC XY: 7150 AN XY: 74446

Gnomad4 AFR AF: 0.0765

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.118

Alfa AF: 0.110 Hom.: 776

Bravo AF: 0.100

Asia WGS AF: 0.0240 AC: 85 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.126

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	clinical testing	GeneDx	Oct 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

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	-0.77
Cadd	Benign	0.037
Dann	Benign	0.44

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: rs11037928; hg19: chr11-44296946; COSMIC: COSV61324527;