4-80008576-A-T

Variant names:

• chr4-80008576-A-T
• rs137852903
• NM_058172.6:c.986T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.30
• Publications: 0 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: 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

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.986T>A	p.Leu329Gln	missense	Exon 12 of 17	NP_477520.2	P58335-4
	ANTXR2	NM_001145794.2		c.986T>A	p.Leu329Gln	missense	Exon 12 of 16	NP_001139266.1	P58335-1
	ANTXR2	NM_001286780.2		c.755T>A	p.Leu252Gln	missense	Exon 12 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.986T>A	p.Leu329Gln	missense	Exon 12 of 17	ENSP00000385575.2	P58335-4
	ANTXR2	ENST00000307333.7	TSL:1	c.986T>A	p.Leu329Gln	missense	Exon 12 of 16	ENSP00000306185.6	P58335-1
	ANTXR2	ENST00000404191.5	TSL:1	c.755T>A	p.Leu252Gln	missense	Exon 12 of 17	ENSP00000384028.1	J3KPY9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455034 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723526

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

African (AFR) AF: 0.00 AC: 0 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 43388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109568

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.52		Loss of stability (P = 0.0205)
MVP		0.80
MPC		0.60
ClinPred		0.99	D
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

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

Other links and lift over

dbSNP: rs137852903; hg19: chr4-80929730;