rs312262693

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_058172.6(ANTXR2):c.1074del(p.Ala359HisfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,607,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

ANTXR2
NM_058172.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.26

Variant links:

Genes affected

ANTXR2 (HGNC:21732): (ANTXR cell adhesion molecule 2) This gene encodes a receptor for anthrax toxin. The protein binds to collagen IV and laminin, suggesting that it may be involved in extracellular matrix adhesion. Mutations in this gene cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ANTXR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-79984830-CA-C is Pathogenic according to our data. Variant chr4-79984830-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 419342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-79984830-CA-C is described in Lovd as [Pathogenic]. Variant chr4-79984830-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ANTXR2	NM_058172.6 linkuse as main transcript	c.1074del	p.Ala359HisfsTer50	frameshift_variant	13/17	ENST00000403729.7
ANTXR2	NM_001145794.2 linkuse as main transcript	c.1074del	p.Ala359HisfsTer50	frameshift_variant	13/16
ANTXR2	NM_001286780.2 linkuse as main transcript	c.843del	p.Ala282HisfsTer50	frameshift_variant	13/17
ANTXR2	NM_001286781.2 linkuse as main transcript	c.843del	p.Ala282HisfsTer50	frameshift_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANTXR2	ENST00000403729.7 linkuse as main transcript	c.1074del	p.Ala359HisfsTer50	frameshift_variant	13/17	1	NM_058172.6	P1	P58335-4

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

151128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000975

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000412

AC:

AN:

242456

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131224

show subpopulations

Gnomad AFR exome

AF:

0.000200

Gnomad AMR exome

AF:

0.0000594

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000573

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1456808

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

724288

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.0000681

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000361

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000265

AC:

AN:

151128

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73680

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000975

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyaline fibromatosis syndrome

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 14, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 28, 2019	This frameshifting variant in exon 13 of 16 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous and as a homozygous change in patients with hyaline fibromatosis syndrome (PMID: 14508707, 21328543). It is found within a hotspot on exon 13 which contains several recurrent frameshift variants that together account for approximately 60% of all pathogenic alleles in ANTXR2 (PMID: 23554269). Functional studies using patient fibroblasts and HeLa cells demonstrated that this variant leads to very low levels of mRNA expression and proteasome-mediated degradation of the mistranslated protein (PMID: 23554269). It is present in the heterozygous state in the gnomAD population database at a frequency of .004% (11/270038) and thus is presumed to be rare. Based on the available evidence, the p.Ala359HisfsTer50 variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000419342, PMID:14508707). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 07, 2023	ACMG classification criteria: PVS1 very strong, PS3 supporting, PM2 moderated, PM3 very strong -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2018

The c.1074delT deletion in the ANTXR2 gene is one of three frameshift variants in the exon 13 hotspotthat accounts for approximately 60% of all pathogenic alleles (Yan et al., 2013). The c.1074delT variant,denoted as c.1602delT due to alternative nomenclature, was reported in the homozygous state in twosiblings in a consanguineous Kuwaiti family with features consistent with infantile systemic hyalinosis(Hanks et al., 2003). It was also also reported previously in the homozygous state in an individual from aconsanguineous Moroccan family with features consistent with juvenile hyaline fibromatosis (Jaouad et al.,2014). Functional studies indicate the c.1074delT deletion leads to abnormalities in the mRNA and proteinfolding, resulting in degradation (Yan et al., 2013). The c.1074delT variant causes a frameshift startingwith codon Alanine 359, changes this amino acid to a Histidine residue, and creates a premature Stopcodon at position 50 of the new reading frame, denoted p.Ala359HisfsX50. This variant is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNAdecay. The c.1074delT deletion was not observed in approximately 5,900 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. We interpret c.1074delT as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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