rs104894196

Variant names:

• chr11-44267585-C-G
• rs104894196
• NM_021926.4:c.815G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-44267585-C-G
• chr11-44267585-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_021926.4(ALX4):​c.815G>C​(p.Arg272Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R272R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALX4 NM_021926.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.14
• Publications: 5 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity ALX4_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_021926.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 11-44267585-C-G is Pathogenic according to our data. Variant chr11-44267585-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5017.Status of the report is no_assertion_criteria_provided, 0 stars.

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.815G>C	p.Arg272Pro	missense	Exon 3 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.815G>C	p.Arg272Pro	missense	Exon 3 of 4	ENSP00000498217.1	Q9H161

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Parietal foramina 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.82		Gain of catalytic residue at R272 (P = 0.0023)
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs104894196; hg19: chr11-44289135;