rs201777848

Positions:

• chr11-44309737-TGCTGCGGCTGCG-T
• chr11-44309737-TGCTGCGGCTGCG-TGCTGCG
• chr11-44309737-TGCTGCGGCTGCG-TGCTGCGGCTGCGGCTGCG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021926.4(ALX4):​c.314_325delCGCAGCCGCAGC​(p.Pro105_Gln108del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,555,108 control chromosomes in the GnomAD database, including 274 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (156 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (118 hom.)
• Consequence: ALX4 NM_021926.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.41

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 11-44309737-TGCTGCGGCTGCG-T is Benign according to our data. Variant chr11-44309737-TGCTGCGGCTGCG-T is described in ClinVar as [Benign]. Clinvar id is 776604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4	c.314_325delCGCAGCCGCAGC	p.Pro105_Gln108del	disruptive_inframe_deletion	1/4	ENST00000652299.1	NP_068745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1	c.314_325delCGCAGCCGCAGC	p.Pro105_Gln108del	disruptive_inframe_deletion	1/4		NM_021926.4	ENSP00000498217.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3765 AN: 151820 Hom.: 156 Cov.: 33

Gnomad AFR AF: 0.0871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00774

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.00498 AC: 778 AN: 156232 Hom.: 29 AF XY: 0.00425 AC XY: 364 AN XY: 85612

Gnomad AFR exome AF: 0.0959

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000992

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00235 AC: 3298 AN: 1403174 Hom.: 118 AF XY: 0.00206 AC XY: 1428 AN XY: 693132

Gnomad4 AFR exome AF: 0.0885

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000416

Gnomad4 OTH exome AF: 0.00510

GnomAD4 genome AF: 0.0248 AC: 3771 AN: 151934 Hom.: 156 Cov.: 33 AF XY: 0.0247 AC XY: 1831 AN XY: 74270

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.00773

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0152

Bravo AF: 0.0272

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201777848; hg19: chr11-44331287;