rs61737295

Positions:

chr11-44275531-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021926.4(ALX4):c.594C>A(p.Leu198Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,174 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 75 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 160 hom. )

Consequence

ALX4
NM_021926.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.277

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 11-44275531-G-T is Benign according to our data. Variant chr11-44275531-G-T is described in ClinVar as [Benign]. Clinvar id is 304707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0232 (3528/152298) while in subpopulation AFR AF= 0.0489 (2032/41560). AF 95% confidence interval is 0.0471. There are 75 homozygotes in gnomad4. There are 1820 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 75 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALX4	NM_021926.4 linkuse as main transcript	c.594C>A	p.Leu198Leu	synonymous_variant	2/4	ENST00000652299.1	NP_068745.2	Q9H161

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALX4	ENST00000652299.1 linkuse as main transcript	c.594C>A	p.Leu198Leu	synonymous_variant	2/4		NM_021926.4	ENSP00000498217.1		Q9H161

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3526

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0551

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00847

Gnomad OTH

AF:

0.0273

GnomAD3 exomes

AF:

0.0135

AC:

3386

AN:

251412

Hom.:

AF XY:

0.0124

AC XY:

1691

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.0538

Gnomad NFE exome

AF:

0.00830

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00953

AC:

13931

AN:

1461876

Hom.:

160

Cov.:

AF XY:

0.00922

AC XY:

6704

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0510

Gnomad4 AMR exome

AF:

0.00682

Gnomad4 ASJ exome

AF:

0.00846

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00267

Gnomad4 FIN exome

AF:

0.0503

Gnomad4 NFE exome

AF:

0.00731

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.0232

AC:

3528

AN:

152298

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1820

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0489

Gnomad4 AMR

AF:

0.0125

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0551

Gnomad4 NFE

AF:

0.00847

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0216

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00889

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Parietal foramina 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

3.2

DANN

Benign

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over