4-79984830-CA-C
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_058172.6(ANTXR2):βc.1074delβ(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 (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 31)
Exomes π: 0.000041 ( 0 hom. )
Consequence
ANTXR2
NM_058172.6 frameshift
NM_058172.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.26
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]
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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 | UniProt |
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ANTXR2 | NM_058172.6 | c.1074del | p.Ala359HisfsTer50 | frameshift_variant | 13/17 | ENST00000403729.7 | |
ANTXR2 | NM_001145794.2 | c.1074del | p.Ala359HisfsTer50 | frameshift_variant | 13/16 | ||
ANTXR2 | NM_001286780.2 | c.843del | p.Ala282HisfsTer50 | frameshift_variant | 13/17 | ||
ANTXR2 | NM_001286781.2 | c.843del | p.Ala282HisfsTer50 | frameshift_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANTXR2 | ENST00000403729.7 | c.1074del | p.Ala359HisfsTer50 | frameshift_variant | 13/17 | 1 | NM_058172.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000265 AC: 4AN: 151128Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000412 AC: 10AN: 242456Hom.: 0 AF XY: 0.0000305 AC XY: 4AN XY: 131224
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GnomAD4 exome AF: 0.0000412 AC: 60AN: 1456808Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 24AN XY: 724288
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GnomAD4 genome AF: 0.0000265 AC: 4AN: 151128Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2AN XY: 73680
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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 | 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, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
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 - |
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 | Baylor Genetics | Nov 14, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at