rs12421995

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 304711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44309759-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALX4	NM_021926.4 link	c.304C>T	p.Pro102Ser	missense_variant	Exon 1 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.304C>T	p.Pro102Ser	missense_variant	Exon 1 of 4		NM_021926.4	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

GnomAD3 exomes

AF:

0.465

AC:

67309

AN:

144702

Hom.:

16664

AF XY:

0.483

AC XY:

38066

AN XY:

78884

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 SAS exome

AF:

0.655

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

Gnomad4 AFR exome

AF:

0.0796

Gnomad4 AMR exome

AF:

0.371

Gnomad4 ASJ exome

AF:

0.520

Gnomad4 EAS exome

AF:

0.452

Gnomad4 SAS exome

AF:

0.649

Gnomad4 FIN exome

AF:

0.431

Gnomad4 NFE exome

AF:

0.442

Gnomad4 OTH exome

AF:

0.439

GnomAD4 genome

AF:

0.344

AC:

52368

AN:

152052

Hom.:

11064

Cov.:

AF XY:

0.350

AC XY:

26004

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0950

Gnomad4 AMR

AF:

0.352

Gnomad4 ASJ

AF:

0.505

Gnomad4 EAS

AF:

0.508

Gnomad4 SAS

AF:

0.636

Gnomad4 FIN

AF:

0.435

Gnomad4 NFE

AF:

0.438

Gnomad4 OTH

AF:

0.354

Alfa

AF:

0.431

Hom.:

9758

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16319823, 12774039) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Parietal foramina 2

Benign:2

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontonasal dysplasia with alopecia and genital anomaly

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

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

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

Varity_R

0.039

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over