rs397514700

Variant names:

• chr2-69075602-C-T
• rs397514700
• NM_032208.3:c.505C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_032208.3(ANTXR1):​c.505C>T​(p.Arg169*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000713180: cell lines from this published case provide evidence supporting that this variant causes GAPO syndrome (reduced RT-PCR products, reductions in relative cDNA expression, absence of protein from skin fibroblasts by immunoblot, and alterations in actin cytoskeleton network by immunofluorescence) (Stranecky 2013).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANTXR1 NM_032208.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.35
• Publications: 6 publications found

Genes affected

ANTXR1 (HGNC:21014): (ANTXR cell adhesion molecule 1) This gene encodes a type I transmembrane protein and is a tumor-specific endothelial marker that has been implicated in colorectal cancer. The encoded protein has been shown to also be a docking protein or receptor for Bacillus anthracis toxin, the causative agent of the disease, anthrax. The binding of the protective antigen (PA) component, of the tripartite anthrax toxin, to this receptor protein mediates delivery of toxin components to the cytosol of cells. Once inside the cell, the other two components of anthrax toxin, edema factor (EF) and lethal factor (LF) disrupt normal cellular processes. Three alternatively spliced variants that encode different protein isoforms have been described. [provided by RefSeq, Oct 2008]

ANTXR1 Gene-Disease associations (from GenCC):

• GAPO syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• capillary infantile hemangioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000713180: cell lines from this published case provide evidence supporting that this variant causes GAPO syndrome (reduced RT-PCR products, reductions in relative cDNA expression, absence of protein from skin fibroblasts by immunoblot, and alterations in actin cytoskeleton network by immunofluorescence) (Stranecky 2013).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-69075602-C-T is Pathogenic according to our data. Variant chr2-69075602-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANTXR1	NM_032208.3	MANE Select	c.505C>T	p.Arg169*	stop_gained	Exon 7 of 18	NP_115584.1	Q9H6X2-1
	ANTXR1	NM_053034.2		c.505C>T	p.Arg169*	stop_gained	Exon 7 of 15	NP_444262.1	Q9H6X2-2
	ANTXR1	NM_001410840.1		c.505C>T	p.Arg169*	stop_gained	Exon 7 of 13	NP_001397769.1	H0YC24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANTXR1	ENST00000303714.9	TSL:1 MANE Select	c.505C>T	p.Arg169*	stop_gained	Exon 7 of 18	ENSP00000301945.4	Q9H6X2-1
	ANTXR1	ENST00000409349.7	TSL:1	c.505C>T	p.Arg169*	stop_gained	Exon 7 of 15	ENSP00000386494.3	Q9H6X2-2
	ANTXR1	ENST00000409829.7	TSL:1	c.505C>T	p.Arg169*	stop_gained	Exon 7 of 13	ENSP00000387058.3	Q9H6X2-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	GAPO syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.76	D
PhyloP100		2.3
Vest4		0.98
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs397514700; hg19: chr2-69302734; COSMIC: COSV58013730; COSMIC: COSV58013730;