4-79984831-AG-AGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_058172.6(ANTXR2):c.1073dupC(p.Ala359CysfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.000126 in 1,605,890 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 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ANTXR2
NM_058172.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.14

Publications

15 publications found

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 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

ANTXR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PP5

Variant 4-79984831-A-AG is Pathogenic according to our data. Variant chr4-79984831-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 2604.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 link	c.1073dupC	p.Ala359CysfsTer13	frameshift_variant	Exon 13 of 17	ENST00000403729.7	NP_477520.2	P58335-4
ANTXR2	NM_001145794.2 link	c.1073dupC	p.Ala359CysfsTer13	frameshift_variant	Exon 13 of 16		NP_001139266.1	P58335-1
ANTXR2	NM_001286780.2 link	c.842dupC	p.Ala282CysfsTer13	frameshift_variant	Exon 13 of 17		NP_001273709.1	P58335J3KPY9Q32Q26
ANTXR2	NM_001286781.2 link	c.842dupC	p.Ala282CysfsTer13	frameshift_variant	Exon 13 of 17		NP_001273710.1	P58335J3KPY9A4FUA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANTXR2	ENST00000403729.7 link	c.1073dupC	p.Ala359CysfsTer13	frameshift_variant	Exon 13 of 17	1	NM_058172.6	ENSP00000385575.2		P58335-4

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000399

AC:

AN:

240676

AF XY:

0.000176

show subpopulations

Gnomad AFR exome

AF:

0.000806

Gnomad AMR exome

AF:

0.000329

Gnomad ASJ exome

AF:

0.00112

Gnomad EAS exome

AF:

0.000749

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000404

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1454062

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

723016

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000120

AC:

AN:

33318

American (AMR)

AF:

0.000227

AC:

AN:

43964

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

25990

East Asian (EAS)

AF:

0.000227

AC:

AN:

39580

South Asian (SAS)

AF:

0.000129

AC:

AN:

85068

European-Finnish (FIN)

AF:

0.000303

AC:

AN:

52856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000108

AC:

120

AN:

1107384

Other (OTH)

AF:

0.000116

AC:

AN:

60144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.374

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000132

AC:

AN:

151828

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41396

American (AMR)

AF:

0.0000656

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.000209

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67920

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000512

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyaline fibromatosis syndrome

Pathogenic:5

Jan 12, 2017

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 is predicted to truncate the ANTXR2 protein by approximately 25%. This variant is well reported in HFS, as a review of the literature revealed at least four compound heterozygotes, and three homozygotes with HFS carried the variant (PMID: 14508707, 21328543, 22383261, 23554269, 26207694, 26335786, 27174544). Additionally, functional studies by Yan et al. revealed that patient fibroblasts with the p.Ala359CysfsTer13 variant had decreased mRNA levels and abnormalities in protein folding (PMID: 23554269). The highest reported allele frequency is 0.00382 in the European (Non-Finnish) population, and one homozygote was found in the African population according to the ExAC database. The allele frequency is higher than predicted based on disease prevalence, and the presence of a homozygote may contradict evidence for pathogenicity. However, based on the combined evidence of reported cases and functional studies, the variant is classified as likely pathogenic. -

Jun 03, 2016

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This individual has been reported in PMCID: PMC5851806 (individual 1). -

Apr 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ANTXR2 c.1073dupC (p.Ala359CysfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but reported in the HGMD database. The variant allele was found at a frequency of 0.0004 in 240676 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ANTXR2 causing Hyaline Fibromatosis Syndrome (0.0004 vs 0.0011), allowing no conclusion about variant significance. c.1073dupC has been reported in the literature as homozgygous and compound heterozygous genotypes in individuals affected with Hyaline Fibromatosis Syndrome (example, PMID 15725249, 12973667, 26335786). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ala359Cysfs*13) in the ANTXR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANTXR2 are known to be pathogenic (PMID: 12973667, 14508707). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with infantile systemic hyalinosis (PMID: 14508707, 28914269). This variant is also known as 1601-1602insC. ClinVar contains an entry for this variant (Variation ID: 2604). For these reasons, this variant has been classified as Pathogenic. -

Jun 26, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; One of three frameshift variants in the exon 13 hotspot that accounts for approximately 60% of all pathogenic alleles (Yan et al., 2013); This variant is associated with the following publications: (PMID: 26207694, 22383261, 26335786, 21328543, 28914269, 29801470, 31455396, 31019026, 14508707, 27174544, 23554269) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

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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