11-44275396-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021926.4(ALX4):c.729G>A(p.Ala243Ala) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.84

Publications

13 publications found

Variant links:

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]

ALX4 Gene-Disease associations (from GenCC):

parietal foramina 2
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
frontonasal dysplasia with alopecia and genital anomaly
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
parietal foramina
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ALX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 304704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ALX4	NM_021926.4 link	c.729G>A	p.Ala243Ala	synonymous_variant	Exon 2 of 4	ENST00000652299.1	NP_068745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1 link	c.729G>A	p.Ala243Ala	synonymous_variant	Exon 2 of 4		NM_021926.4	ENSP00000498217.1

Frequencies

GnomAD3 genomes

AF:

0.0993

AC:

15106

AN:

152120

Hom.:

810

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0899

AC:

22601

AN:

251386

AF XY:

0.0902

show subpopulations

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 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.:

AF XY:

0.105

AC XY:

76393

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0753

AC:

2522

AN:

33480

American (AMR)

AF:

0.0713

AC:

3188

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2741

AN:

26134

East Asian (EAS)

AF:

0.000907

AC:

AN:

39700

South Asian (SAS)

AF:

0.0365

AC:

3151

AN:

86256

European-Finnish (FIN)

AF:

0.0995

AC:

5316

AN:

53414

Middle Eastern (MID)

AF:

0.190

AC:

1095

AN:

5768

European-Non Finnish (NFE)

AF:

0.118

AC:

131448

AN:

1112000

Other (OTH)

AF:

0.106

AC:

6383

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

8427

16854

25282

33709

42136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4582

9164

13746

18328

22910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0993

AC:

15110

AN:

152238

Hom.:

811

Cov.:

AF XY:

0.0960

AC XY:

7150

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0765

AC:

3179

AN:

41538

American (AMR)

AF:

0.103

AC:

1572

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

374

AN:

3470

East Asian (EAS)

AF:

0.00212

AC:

AN:

5182

South Asian (SAS)

AF:

0.0332

AC:

160

AN:

4824

European-Finnish (FIN)

AF:

0.102

AC:

1082

AN:

10614

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.123

AC:

8351

AN:

67992

Other (OTH)

AF:

0.118

AC:

250

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

702

1403

2105

2806

3508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.108

Hom.:

937

Bravo

AF:

0.100

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.126

EpiControl

AF:

0.126

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parietal foramina 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.44

PhyloP100

-3.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over