11-44309959-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021926.4(ALX4):c.104G>C(p.Arg35Thr) variant causes a missense change. The variant allele was found at a frequency of 0.497 in 1,592,832 control chromosomes in the GnomAD database, including 202,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 15307 hom., cov: 34)

Exomes 𝑓: 0.50 ( 187340 hom. )

Consequence

ALX4
NM_021926.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.79

Publications

33 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 (MetaRNN=2.7497963E-6).

BP6

Variant 11-44309959-C-G is Benign according to our data. Variant chr11-44309959-C-G is described in ClinVar as Benign. ClinVar VariationId is 304715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021926.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX4	NM_021926.4	MANE Select	c.104G>C	p.Arg35Thr	missense	Exon 1 of 4	NP_068745.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX4	ENST00000652299.1	MANE Select	c.104G>C	p.Arg35Thr	missense	Exon 1 of 4	ENSP00000498217.1

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

66208

AN:

152028

Hom.:

15304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.299

Gnomad AMI

AF:

0.522

Gnomad AMR

AF:

0.394

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.767

Gnomad FIN

AF:

0.467

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.487

Gnomad OTH

AF:

0.426

GnomAD2 exomes

AF:

0.506

AC:

107636

AN:

212748

AF XY:

0.524

show subpopulations

Gnomad AFR exome

AF:

0.294

Gnomad AMR exome

AF:

0.404

Gnomad ASJ exome

AF:

0.559

Gnomad EAS exome

AF:

0.525

Gnomad FIN exome

AF:

0.460

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.496

GnomAD4 exome

AF:

0.504

AC:

725993

AN:

1440686

Hom.:

187340

Cov.:

AF XY:

0.513

AC XY:

366518

AN XY:

714678

show subpopulations

African (AFR)

AF:

0.285

AC:

9418

AN:

33066

American (AMR)

AF:

0.398

AC:

16665

AN:

41870

Ashkenazi Jewish (ASJ)

AF:

0.560

AC:

14383

AN:

25694

East Asian (EAS)

AF:

0.457

AC:

17653

AN:

38608

South Asian (SAS)

AF:

0.765

AC:

63584

AN:

83114

European-Finnish (FIN)

AF:

0.466

AC:

23997

AN:

51520

Middle Eastern (MID)

AF:

0.473

AC:

2721

AN:

5750

European-Non Finnish (NFE)

AF:

0.497

AC:

547629

AN:

1101568

Other (OTH)

AF:

0.503

AC:

29943

AN:

59496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

24407

48813

73220

97626

122033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16102

32204

48306

64408

80510

<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:

0.435

AC:

66246

AN:

152146

Hom.:

15307

Cov.:

AF XY:

0.439

AC XY:

32677

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.299

AC:

12416

AN:

41522

American (AMR)

AF:

0.394

AC:

6024

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1897

AN:

3472

East Asian (EAS)

AF:

0.513

AC:

2647

AN:

5164

South Asian (SAS)

AF:

0.767

AC:

3695

AN:

4818

European-Finnish (FIN)

AF:

0.467

AC:

4940

AN:

10586

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.487

AC:

33120

AN:

67966

Other (OTH)

AF:

0.430

AC:

909

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1953

3906

5858

7811

9764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

634

1268

1902

2536

3170

<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:

0.489

Hom.:

14308

Bravo

AF:

0.416

TwinsUK

AF:

0.499

AC:

1850

ALSPAC

AF:

0.498

AC:

1921

ESP6500AA

AF:

0.301

AC:

1324

ESP6500EA

AF:

0.487

AC:

4189

ExAC

AF:

0.482

AC:

57868

Asia WGS

AF:

0.619

AC:

2154

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Parietal foramina 2 (2)

Frontonasal dysplasia with alopecia and genital anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0000027

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

5.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.022

Polyphen

0.44

Vest4

0.32

MPC

1.1

ClinPred

0.042

GERP RS

4.6

PromoterAI

0.29

Neutral

(source)

Varity_R

0.60

gMVP

0.72

Mutation Taster

=39/61

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over