rs11037928

Variant names:

• chr11-44275396-C-T
• rs11037928
• NM_021926.4:c.729G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-44275396-C-T
• chr11-44275396-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021926.4(ALX4):​c.729G>A​(p.Ala243Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,614,110 control chromosomes in the GnomAD database, including 10,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (811 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9232 hom.)
• Consequence: ALX4 NM_021926.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.84
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-44275396-C-T is Benign according to our data. Variant chr11-44275396-C-T is described in ClinVar as Benign. ClinVar VariationId is 304704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 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.729G>A	p.Ala243Ala	synonymous	Exon 2 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.729G>A	p.Ala243Ala	synonymous	Exon 2 of 4	ENSP00000498217.1	Q9H161

Frequencies

GnomAD3 genomes AF: 0.0993 AC: 15106 AN: 152120 Hom.: 810 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.0899 AC: 22601 AN: 251386 AF XY: 0.0902

Gnomad AFR exome AF: 0.0751

Gnomad AMR exome AF: 0.0669

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.00141

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.107 AC: 155880 AN: 1461872 Hom.: 9232 Cov.: 35 AF XY: 0.105 AC XY: 76393 AN XY: 727236

African (AFR) AF: 0.0753 AC: 2522 AN: 33480

American (AMR) AF: 0.0713 AC: 3188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2741 AN: 26134

East Asian (EAS) AF: 0.000907 AC: 36 AN: 39700

South Asian (SAS) AF: 0.0365 AC: 3151 AN: 86256

European-Finnish (FIN) AF: 0.0995 AC: 5316 AN: 53414

Middle Eastern (MID) AF: 0.190 AC: 1095 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 131448 AN: 1112000

Other (OTH) AF: 0.106 AC: 6383 AN: 60396

GnomAD4 genome AF: 0.0993 AC: 15110 AN: 152238 Hom.: 811 Cov.: 33 AF XY: 0.0960 AC XY: 7150 AN XY: 74446

African (AFR) AF: 0.0765 AC: 3179 AN: 41538

American (AMR) AF: 0.103 AC: 1572 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5182

South Asian (SAS) AF: 0.0332 AC: 160 AN: 4824

European-Finnish (FIN) AF: 0.102 AC: 1082 AN: 10614

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8351 AN: 67992

Other (OTH) AF: 0.118 AC: 250 AN: 2116

Alfa AF: 0.108 Hom.: 937

Bravo AF: 0.100

Asia WGS AF: 0.0240 AC: 85 AN: 3478

EpiCase AF: 0.126

EpiControl AF: 0.126

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Parietal foramina 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.037
DANN	Benign	0.44
PhyloP100		-3.8
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11037928; hg19: chr11-44296946; COSMIC: COSV61324527;