rs12421995

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.304C>T(p.Pro102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,546,934 control chromosomes in the GnomAD database, including 153,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 11064 hom., cov: 33)

Exomes 𝑓: 0.44 ( 142592 hom. )

Consequence

ALX4
NM_021926.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.36

Publications

23 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
frontonasal dysplasia with alopecia and genital anomaly
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), 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=6.709345E-6).

BP6

Variant 11-44309759-G-A is Benign according to our data. Variant chr11-44309759-G-A is described in ClinVar as Benign. ClinVar VariationId is 304711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.617 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX4	NM_021926.4	MANE Select	c.304C>T	p.Pro102Ser	missense	Exon 1 of 4	NP_068745.2	Q9H161

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX4	ENST00000652299.1	MANE Select	c.304C>T	p.Pro102Ser	missense	Exon 1 of 4	ENSP00000498217.1	Q9H161

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52368

AN:

151942

Hom.:

11072

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0951

Gnomad AMI

AF:

0.425

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.636

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.349

GnomAD2 exomes

AF:

0.465

AC:

67309

AN:

144702

AF XY:

0.483

show subpopulations

Gnomad AFR exome

AF:

0.0918

Gnomad AMR exome

AF:

0.382

Gnomad ASJ exome

AF:

0.527

Gnomad EAS exome

AF:

0.531

Gnomad FIN exome

AF:

0.433

Gnomad NFE exome

AF:

0.453

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.445

AC:

620533

AN:

1394882

Hom.:

142592

Cov.:

AF XY:

0.453

AC XY:

311565

AN XY:

688034

show subpopulations

African (AFR)

AF:

0.0796

AC:

2476

AN:

31118

American (AMR)

AF:

0.371

AC:

13222

AN:

35640

Ashkenazi Jewish (ASJ)

AF:

0.520

AC:

13021

AN:

25058

East Asian (EAS)

AF:

0.452

AC:

16123

AN:

35672

South Asian (SAS)

AF:

0.649

AC:

51561

AN:

79458

European-Finnish (FIN)

AF:

0.431

AC:

20356

AN:

47236

Middle Eastern (MID)

AF:

0.420

AC:

1964

AN:

4676

European-Non Finnish (NFE)

AF:

0.442

AC:

476454

AN:

1078312

Other (OTH)

AF:

0.439

AC:

25356

AN:

57712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

20779

41557

62336

83114

103893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14528

29056

43584

58112

72640

<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:

0.344

AC:

52368

AN:

152052

Hom.:

11064

Cov.:

AF XY:

0.350

AC XY:

26004

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0950

AC:

3943

AN:

41506

American (AMR)

AF:

0.352

AC:

5381

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1750

AN:

3468

East Asian (EAS)

AF:

0.508

AC:

2609

AN:

5136

South Asian (SAS)

AF:

0.636

AC:

3070

AN:

4828

European-Finnish (FIN)

AF:

0.435

AC:

4594

AN:

10570

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.438

AC:

29782

AN:

67940

Other (OTH)

AF:

0.354

AC:

746

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1629

3258

4887

6516

8145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.432

Hom.:

15532

Bravo

AF:

0.322

TwinsUK

AF:

0.439

AC:

1627

ALSPAC

AF:

0.444

AC:

1711

ExAC

AF:

0.400

AC:

31791

Asia WGS

AF:

0.550

AC:

1903

AN:

3462

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Parietal foramina 2 (2)

Frontonasal dysplasia with alopecia and genital anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.17

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.79

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0000067

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.55

PhyloP100

1.4

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.36

REVEL

Benign

0.025

Sift

Uncertain

0.029

Sift4G

Benign

0.59

Polyphen

0.0060

Vest4

0.078

MPC

0.30

ClinPred

0.0015

GERP RS

2.1

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.039

gMVP

0.21

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over