11-44265016-G-C

Variant names:

• chr11-44265016-G-C
• rs3802805
• NM_021926.4:c.1074C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021926.4(ALX4):​c.1074C>G​(p.His358Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H358H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALX4 NM_021926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55
• Publications: 19 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

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.1074C>G	p.His358Gln	missense	Exon 4 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.1074C>G	p.His358Gln	missense	Exon 4 of 4	ENSP00000498217.1	Q9H161

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.052
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.46
Sift	Benign	0.072	T
Sift4G	Benign	0.081	T
Polyphen		0.45	B
Vest4		0.61
MutPred		0.17		Loss of glycosylation at S357 (P = 0.0965)
MVP		0.95
MPC		0.99
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.26
gMVP		0.74
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3802805; hg19: chr11-44286566;