rs312262693

Variant names:

• chr4-79984830-CA-C
• rs312262693
• NM_058172.6:c.1074delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_058172.6(ANTXR2):​c.1074delT​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.26
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• hyaline fibromatosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• juvenile hyaline fibromatosis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• infantile systemic hyalinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANTXR2	NM_058172.6	c.1074delT	p.Ala359HisfsTer50	frameshift_variant	Exon 13 of 17	ENST00000403729.7	NP_477520.2
ANTXR2	NM_001145794.2	c.1074delT	p.Ala359HisfsTer50	frameshift_variant	Exon 13 of 16		NP_001139266.1
ANTXR2	NM_001286780.2	c.843delT	p.Ala282HisfsTer50	frameshift_variant	Exon 13 of 17		NP_001273709.1
ANTXR2	NM_001286781.2	c.843delT	p.Ala282HisfsTer50	frameshift_variant	Exon 13 of 17		NP_001273710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANTXR2	ENST00000403729.7	c.1074delT	p.Ala359HisfsTer50	frameshift_variant	Exon 13 of 17	1	NM_058172.6	ENSP00000385575.2

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 151128 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000412 AC: 10 AN: 242456 AF XY: 0.0000305

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 60 AN: 1456808 Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 24 AN XY: 724288

African (AFR) AF: 0.000210 AC: 7 AN: 33404

American (AMR) AF: 0.0000681 AC: 3 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26028

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39628

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1109224

Other (OTH) AF: 0.0000332 AC: 2 AN: 60236

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 151128 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73680

African (AFR) AF: 0.0000487 AC: 2 AN: 41088

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.0000975 AC: 1 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyaline fibromatosis syndrome Pathogenic:8

May 28, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 07, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PM2 moderated, PM3 very strong -

-

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1

Feb 15, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.3
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs312262693; hg19: chr4-80905984;