rs3824915

chr11-44309959-C-Gchr11-44309959-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.79

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]

ACMG classification

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	UniProt
ALX4	NM_021926.4	c.104G>C	p.Arg35Thr	missense_variant	1/4	ENST00000652299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX4	ENST00000652299.1	c.104G>C	p.Arg35Thr	missense_variant	1/4		NM_021926.4	P1

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66208 AN: 152028 Hom.: 15304 Cov.: 34

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

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.: 86 AF XY: 0.513 AC XY: 366518 AN XY: 714678

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.: 34 AF XY: 0.439 AC XY: 32677 AN XY: 74378

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	27
Dann	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.0000040	P
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.022	D
Polyphen		0.44	B
Vest4		0.32
MPC		1.1
ClinPred		0.042	T
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

Other links and lift over

dbSNP: rs3824915; hg19: chr11-44331509; COSMIC: COSV61327884;