NM_021926.4:c.1074C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021926.4(ALX4):​c.1074C>T​(p.His358His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,612,836 control chromosomes in the GnomAD database, including 101,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8218 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93155 hom.)
• Consequence: ALX4 NM_021926.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-44265016-G-A is Benign according to our data. Variant chr11-44265016-G-A is described in ClinVar as Benign. ClinVar VariationId is 304701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 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.1074C>T	p.His358His	synonymous	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>T	p.His358His	synonymous	Exon 4 of 4	ENSP00000498217.1	Q9H161

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46686 AN: 152044 Hom.: 8203 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.373 AC: 93097 AN: 249426 AF XY: 0.369

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.350 AC: 511825 AN: 1460674 Hom.: 93155 Cov.: 72 AF XY: 0.351 AC XY: 254850 AN XY: 726672

African (AFR) AF: 0.153 AC: 5106 AN: 33476

American (AMR) AF: 0.558 AC: 24928 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5984 AN: 26122

East Asian (EAS) AF: 0.521 AC: 20675 AN: 39694

South Asian (SAS) AF: 0.393 AC: 33905 AN: 86252

European-Finnish (FIN) AF: 0.343 AC: 17966 AN: 52388

Middle Eastern (MID) AF: 0.273 AC: 1572 AN: 5764

European-Non Finnish (NFE) AF: 0.342 AC: 380648 AN: 1111892

Other (OTH) AF: 0.348 AC: 21041 AN: 60376

GnomAD4 genome AF: 0.307 AC: 46736 AN: 152162 Hom.: 8218 Cov.: 33 AF XY: 0.313 AC XY: 23267 AN XY: 74360

African (AFR) AF: 0.166 AC: 6883 AN: 41540

American (AMR) AF: 0.453 AC: 6934 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3466

East Asian (EAS) AF: 0.534 AC: 2761 AN: 5174

South Asian (SAS) AF: 0.386 AC: 1857 AN: 4812

European-Finnish (FIN) AF: 0.347 AC: 3671 AN: 10592

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22655 AN: 67964

Other (OTH) AF: 0.341 AC: 721 AN: 2114

Alfa AF: 0.325 Hom.: 11211

Bravo AF: 0.312

Asia WGS AF: 0.477 AC: 1655 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.326

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Parietal foramina 2 (2)
-	-	1	Frontonasal dysplasia with alopecia and genital anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.1
DANN	Uncertain	0.98
PhyloP100		2.5
Mutation Taster		=100/0	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: rs3802805; hg19: chr11-44286566; COSMIC: COSV61327994;