Genetic Variant NM_058172.6:c.986T>A (chr4-80008576-A-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_058172.6(ANTXR2):c.986T>A(p.Leu329Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L329R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANTXR2
NM_058172.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.30

Publications

0 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-80008576-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2601.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANTXR2	NM_058172.6 link	c.986T>A	p.Leu329Gln	missense_variant	Exon 12 of 17	ENST00000403729.7	NP_477520.2	P58335-4
ANTXR2	NM_001145794.2 link	c.986T>A	p.Leu329Gln	missense_variant	Exon 12 of 16		NP_001139266.1	P58335-1
ANTXR2	NM_001286780.2 link	c.755T>A	p.Leu252Gln	missense_variant	Exon 12 of 17		NP_001273709.1	P58335J3KPY9Q32Q26
ANTXR2	NM_001286781.2 link	c.755T>A	p.Leu252Gln	missense_variant	Exon 12 of 17		NP_001273710.1	P58335J3KPY9A4FUA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANTXR2	ENST00000403729.7 link	c.986T>A	p.Leu329Gln	missense_variant	Exon 12 of 17	1	NM_058172.6	ENSP00000385575.2		P58335-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455034

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723526

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.00

AC:

AN:

43388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39238

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109568

Other (OTH)

AF:

0.00

AC:

AN:

60116

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;.;.;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

T;D;T;T

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.4

M;.;.;M

PhyloP100

6.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.82

MutPred

0.52

Loss of stability (P = 0.0205);.;.;Loss of stability (P = 0.0205);

MVP

0.80

MPC

0.60

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.62

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over