NM_021926.4:c.304C>A

Variant names:

• chr11-44309759-G-T
• rs12421995
• NM_021926.4:c.304C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021926.4(ALX4):​c.304C>A​(p.Pro102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P102S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ALX4 NM_021926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1397439).

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.304C>A	p.Pro102Thr	missense	Exon 1 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.304C>A	p.Pro102Thr	missense	Exon 1 of 4	ENSP00000498217.1	Q9H161

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394978 Hom.: 0 Cov.: 70 AF XY: 0.00000145 AC XY: 1 AN XY: 688094

African (AFR) AF: 0.00 AC: 0 AN: 31120

American (AMR) AF: 0.00 AC: 0 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25060

East Asian (EAS) AF: 0.00 AC: 0 AN: 35674

South Asian (SAS) AF: 0.00 AC: 0 AN: 79460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4682

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078362

Other (OTH) AF: 0.00 AC: 0 AN: 57714

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.020
Sift	Uncertain	0.011	D
Sift4G	Benign	0.42	T
Polyphen		0.014	B
Vest4		0.23
MutPred		0.20		Gain of phosphorylation at P102 (P = 0.0056)
MVP		0.62
MPC		0.33
ClinPred		0.070	T
GERP RS		2.1
PromoterAI		-0.012	Neutral
Varity_R		0.065
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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: rs12421995; hg19: chr11-44331309;