chr11-44275520-A-G

Position:

• chr11-44275520-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021926.4(ALX4):​c.605T>C​(p.Leu202Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ALX4 NM_021926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.55

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22297314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4	c.605T>C	p.Leu202Ser	missense_variant	2/4	ENST00000652299.1	NP_068745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1	c.605T>C	p.Leu202Ser	missense_variant	2/4		NM_021926.4	ENSP00000498217.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.31
Sift	Benign	0.069	T
Sift4G	Benign	0.72	T
Polyphen		0.0070	B
Vest4		0.32
MutPred		0.29		Gain of phosphorylation at L202 (P = 0.0031);
MVP		0.96
MPC		0.51
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.11
gMVP		0.47

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: rs150424138; hg19: chr11-44297070;