NM_021926.4:c.594C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021926.4(ALX4):c.594C>A(p.Leu198Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,174 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 75 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 160 hom. )

Consequence

ALX4
NM_021926.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.277

Publications

5 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 11-44275531-G-T is Benign according to our data. Variant chr11-44275531-G-T is described in ClinVar as Benign. ClinVar VariationId is 304707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0232 (3528/152298) while in subpopulation AFR AF = 0.0489 (2032/41560). AF 95% confidence interval is 0.0471. There are 75 homozygotes in GnomAd4. There are 1820 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 75 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALX4	NM_021926.4 link	c.594C>A	p.Leu198Leu	synonymous_variant	Exon 2 of 4	ENST00000652299.1	NP_068745.2	Q9H161

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1 link	c.594C>A	p.Leu198Leu	synonymous_variant	Exon 2 of 4		NM_021926.4	ENSP00000498217.1		Q9H161

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3526

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0551

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00847

Gnomad OTH

AF:

0.0273

GnomAD2 exomes

AF:

0.0135

AC:

3386

AN:

251412

AF XY:

0.0124

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0538

Gnomad NFE exome

AF:

0.00830

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00953

AC:

13931

AN:

1461876

Hom.:

160

Cov.:

AF XY:

0.00922

AC XY:

6704

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0510

AC:

1709

AN:

33480

American (AMR)

AF:

0.00682

AC:

305

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.00267

AC:

230

AN:

86256

European-Finnish (FIN)

AF:

0.0503

AC:

2686

AN:

53420

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00731

AC:

8128

AN:

1111996

Other (OTH)

AF:

0.0102

AC:

618

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

893

1786

2680

3573

4466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.0232

AC:

3528

AN:

152298

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1820

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0489

AC:

2032

AN:

41560

American (AMR)

AF:

0.0125

AC:

192

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00269

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0551

AC:

585

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00847

AC:

576

AN:

68018

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

179

358

537

716

895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0183

Hom.:

Bravo

AF:

0.0216

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00889

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2019

GeneDx

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

- -

Parietal foramina 2

Benign:1

Jan 12, 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

-0.57

CADD

Benign

3.2

(source)

DANN

Benign

0.75

PhyloP100

-0.28

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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