4-79984831-AG-AGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000996054: "patient fibroblasts with the p.Ala359CysfsTer13 variant had decreased mRNA levels and abnormalities in protein folding" (PMID:23554269)". 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:8

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: 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

ANTXR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 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: SCV000996054: "patient fibroblasts with the p.Ala359CysfsTer13 variant had decreased mRNA levels and abnormalities in protein folding" (PMID: 23554269)

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANTXR2	NM_058172.6	MANE Select	c.1073dupC	p.Ala359CysfsTer13	frameshift	Exon 13 of 17	NP_477520.2	P58335-4
ANTXR2	NM_001145794.2		c.1073dupC	p.Ala359CysfsTer13	frameshift	Exon 13 of 16	NP_001139266.1	P58335-1
ANTXR2	NM_001286780.2		c.842dupC	p.Ala282CysfsTer13	frameshift	Exon 13 of 17	NP_001273709.1	J3KPY9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANTXR2	ENST00000403729.7	TSL:1 MANE Select	c.1073dupC	p.Ala359CysfsTer13	frameshift	Exon 13 of 17	ENSP00000385575.2	P58335-4
ANTXR2	ENST00000307333.7	TSL:1	c.1073dupC	p.Ala359CysfsTer13	frameshift	Exon 13 of 16	ENSP00000306185.6	P58335-1
ANTXR2	ENST00000404191.5	TSL:1	c.842dupC	p.Ala282CysfsTer13	frameshift	Exon 13 of 17	ENSP00000384028.1	J3KPY9

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyaline fibromatosis syndrome (6)

not provided (2)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over