rs61737295

chr11-44275531-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021926.4(ALX4):c.594C>A(p.Leu198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,174 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (75 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (160 hom.)
• Consequence: ALX4 NM_021926.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.277

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 (BayesDel_noAF=-0.57).
• BP6: Variant 11-44275531-G-T is Benign according to our data. Variant chr11-44275531-G-T is described in ClinVar as [Benign]. Clinvar id is 304707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0232 (3528/152298) while in subpopulation AFR AF= 0.0489 (2032/41560). AF 95% confidence interval is 0.0471. There are 75 homozygotes in gnomad4. There are 1820 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 76 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX4	NM_021926.4	c.594C>A	p.Leu198=	synonymous_variant	2/4	ENST00000652299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX4	ENST00000652299.1	c.594C>A	p.Leu198=	synonymous_variant	2/4		NM_021926.4	P1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3526 AN: 152180 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0135 AC: 3386 AN: 251412 Hom.: 70 AF XY: 0.0124 AC XY: 1691 AN XY: 135902

Gnomad AFR exome AF: 0.0497

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.0538

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00953 AC: 13931 AN: 1461876 Hom.: 160 Cov.: 37 AF XY: 0.00922 AC XY: 6704 AN XY: 727246

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.00682

Gnomad4 ASJ exome AF: 0.00846

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00267

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.00731

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.0232 AC: 3528 AN: 152298 Hom.: 75 Cov.: 33 AF XY: 0.0244 AC XY: 1820 AN XY: 74458

Gnomad4 AFR AF: 0.0489

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0551

Gnomad4 NFE AF: 0.00847

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0154 Hom.: 13

Bravo AF: 0.0216

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00889

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2019	- -

Parietal foramina 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	3.2
Dann	Benign	0.75

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: rs61737295; hg19: chr11-44297081;