rs3824915

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 304715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44309959-C-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4 linkuse as main transcript	c.104G>C	p.Arg35Thr	missense_variant	1/4	ENST00000652299.1	NP_068745.2	Q9H161

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1 linkuse as main transcript	c.104G>C	p.Arg35Thr	missense_variant	1/4		NM_021926.4	ENSP00000498217.1		Q9H161

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

GnomAD3 exomes

AF:

0.506

AC:

107636

AN:

212748

Hom.:

28540

AF XY:

0.524

AC XY:

60525

AN XY:

115484

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 SAS exome

AF:

0.769

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

Gnomad4 AFR exome

AF:

0.285

Gnomad4 AMR exome

AF:

0.398

Gnomad4 ASJ exome

AF:

0.560

Gnomad4 EAS exome

AF:

0.457

Gnomad4 SAS exome

AF:

0.765

Gnomad4 FIN exome

AF:

0.466

Gnomad4 NFE exome

AF:

0.497

Gnomad4 OTH exome

AF:

0.503

GnomAD4 genome

AF:

0.435

AC:

66246

AN:

152146

Hom.:

15307

Cov.:

AF XY:

0.439

AC XY:

32677

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.299

Gnomad4 AMR

AF:

0.394

Gnomad4 ASJ

AF:

0.546

Gnomad4 EAS

AF:

0.513

Gnomad4 SAS

AF:

0.767

Gnomad4 FIN

AF:

0.467

Gnomad4 NFE

AF:

0.487

Gnomad4 OTH

AF:

0.430

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Parietal foramina 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Frontonasal dysplasia with alopecia and genital anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

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

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

Varity_R

0.60

gMVP

0.72

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