chr4-79984830-CA-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000567074: Functional studies indicate the c.1074delT deletion leads to abnormalities in the mRNA and protein folding, resulting in degradation (Yan et al., 2013)." and additional evidence is available in ClinVar. 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: ClinGen, Labcorp Genetics (formerly Invitae)
• 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 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: SCV000567074: Functional studies indicate the c.1074delT deletion leads to abnormalities in the mRNA and protein folding, resulting in degradation (Yan et al., 2013).; SCV001445921: 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).
• 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 VariationId is 419342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058172.6. 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
	ANTXR2	NM_058172.6	MANE Select	c.1074delT	p.Ala359HisfsTer50	frameshift	Exon 13 of 17	NP_477520.2	P58335-4
	ANTXR2	NM_001145794.2		c.1074delT	p.Ala359HisfsTer50	frameshift	Exon 13 of 16	NP_001139266.1	P58335-1
	ANTXR2	NM_001286780.2		c.843delT	p.Ala282HisfsTer50	frameshift	Exon 13 of 17	NP_001273709.1	J3KPY9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANTXR2	ENST00000403729.7	TSL:1 MANE Select	c.1074delT	p.Ala359HisfsTer50	frameshift	Exon 13 of 17	ENSP00000385575.2	P58335-4
	ANTXR2	ENST00000307333.7	TSL:1	c.1074delT	p.Ala359HisfsTer50	frameshift	Exon 13 of 16	ENSP00000306185.6	P58335-1
	ANTXR2	ENST00000404191.5	TSL:1	c.843delT	p.Ala282HisfsTer50	frameshift	Exon 13 of 17	ENSP00000384028.1	J3KPY9

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Hyaline fibromatosis syndrome (8)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;