4-79984831-AG-AGG

Position:

• chr4-79984831-AG-AGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_058172.6(ANTXR2):​c.1073_1074insC​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.14

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]

ACMG classification

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 4-79984831-A-AG is Pathogenic according to our data. Variant chr4-79984831-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 2604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANTXR2	NM_058172.6	c.1073_1074insC	p.Ala359CysfsTer13	frameshift_variant	13/17	ENST00000403729.7	NP_477520.2
ANTXR2	NM_001145794.2	c.1073_1074insC	p.Ala359CysfsTer13	frameshift_variant	13/16		NP_001139266.1
ANTXR2	NM_001286780.2	c.842_843insC	p.Ala282CysfsTer13	frameshift_variant	13/17		NP_001273709.1
ANTXR2	NM_001286781.2	c.842_843insC	p.Ala282CysfsTer13	frameshift_variant	13/17		NP_001273710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANTXR2	ENST00000403729.7	c.1073_1074insC	p.Ala359CysfsTer13	frameshift_variant	13/17	1	NM_058172.6	ENSP00000385575	P1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151712 Hom.: 0 Cov.: 31

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

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1454062 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 97 AN XY: 723016

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151828 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74236

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000512 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyaline fibromatosis syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2022	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. -
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	Jan 12, 2017	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. -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Jun 03, 2016	This individual has been reported in PMCID: PMC5851806 (individual 1). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	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

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

Other links and lift over

dbSNP: rs312262690; hg19: chr4-80905985;