NM_021926.4:c.314_325delCGCAGCCGCAGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.41

Publications

2 publications found

Variant links:

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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
frontonasal dysplasia with alopecia and genital anomaly
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
parietal foramina
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ALX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ALX4	NM_021926.4 link	c.314_325delCGCAGCCGCAGC	p.Pro105_Gln108del	disruptive_inframe_deletion	Exon 1 of 4	ENST00000652299.1	NP_068745.2	Q9H161

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1 link	c.314_325delCGCAGCCGCAGC	p.Pro105_Gln108del	disruptive_inframe_deletion	Exon 1 of 4		NM_021926.4	ENSP00000498217.1		Q9H161

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3765

AN:

151820

Hom.:

156

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00498

AC:

778

AN:

156232

AF XY:

0.00425

show subpopulations

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 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

show subpopulations

African (AFR)

AF:

0.0885

AC:

2781

AN:

31412

American (AMR)

AF:

0.00428

AC:

159

AN:

37162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25128

East Asian (EAS)

AF:

0.00

AC:

AN:

36232

South Asian (SAS)

AF:

0.000125

AC:

AN:

80286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47700

Middle Eastern (MID)

AF:

0.00152

AC:

AN:

4598

European-Non Finnish (NFE)

AF:

0.0000416

AC:

AN:

1082634

Other (OTH)

AF:

0.00510

AC:

296

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

166

332

499

665

831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0248

AC:

3771

AN:

151934

Hom.:

156

Cov.:

AF XY:

0.0247

AC XY:

1831

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.0869

AC:

3602

AN:

41428

American (AMR)

AF:

0.00773

AC:

118

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000625

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67936

Other (OTH)

AF:

0.0152

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

161

322

484

645

806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0272

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.4

Mutation Taster

=176/24

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over