Genetic Variant PAX9:p.Ile87Leu (chr14-36663151-A-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001372076.1(PAX9):c.259A>C(p.Ile87Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 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. I87F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAX9
NM_001372076.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.31

Publications

0 publications found

Variant links:

Genes affected

PAX9 (HGNC:8623): (paired box 9) This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3. [provided by RefSeq, Sep 2015]

PAX9 Gene-Disease associations (from GenCC):

tooth agenesis, selective, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PAX9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a DNA_binding_region Paired (size 126) in uniprot entity PAX9_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_001372076.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX9	NM_001372076.1 link	c.259A>C	p.Ile87Leu	missense_variant	Exon 2 of 4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4 link	c.259A>C	p.Ile87Leu	missense_variant	Exon 3 of 5		NP_006185.1	P55771Q2L4T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAX9	ENST00000361487.7 link	c.259A>C	p.Ile87Leu	missense_variant	Exon 2 of 4	1	NM_001372076.1	ENSP00000355245.6	P55771
PAX9	ENST00000402703.6 link	c.259A>C	p.Ile87Leu	missense_variant	Exon 3 of 5	5		ENSP00000384817.2	P55771
PAX9	ENST00000554201.1 link	n.578A>C		non_coding_transcript_exon_variant	Exon 1 of 3	2
PAX9	ENST00000555639.2 link	c.*8A>C		downstream_gene_variant		5		ENSP00000501203.1	A0A669KBA7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;.

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.65

P;P

Vest4

0.79

MutPred

0.82

Loss of methylation at K91 (P = 0.0939);Loss of methylation at K91 (P = 0.0939);

MVP

0.93

MPC

3.0

ClinPred

0.99

GERP RS

5.2

Varity_R

0.90

gMVP

0.88

Mutation Taster

=189/111

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over