dbSNP rs4904210: PAX9:p.Ala240Thr (chr14-36666548-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001372076.1(PAX9):c.718G>A(p.Ala240Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. A240P) has been classified as Benign.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAX9
NM_001372076.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

Publications

54 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25183743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX9	NM_001372076.1 link	c.718G>A	p.Ala240Thr	missense_variant	Exon 3 of 4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4 link	c.718G>A	p.Ala240Thr	missense_variant	Exon 4 of 5		NP_006185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PAX9	ENST00000361487.7 link	c.718G>A	p.Ala240Thr	missense_variant	Exon 3 of 4	1	NM_001372076.1	ENSP00000355245.6
PAX9	ENST00000402703.6 link	c.718G>A	p.Ala240Thr	missense_variant	Exon 4 of 5	5		ENSP00000384817.2
PAX9	ENST00000554201.1 link	n.1037G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2
PAX9	ENST00000557107.1 link	n.559G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1433202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710138

African (AFR)

AF:

0.00

AC:

AN:

32918

American (AMR)

AF:

0.00

AC:

AN:

40826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25568

East Asian (EAS)

AF:

0.00

AC:

AN:

38196

South Asian (SAS)

AF:

0.00

AC:

AN:

82024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097750

Other (OTH)

AF:

0.00

AC:

AN:

59292

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

T;.;T

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

2.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.55

T;T;T

Vest4

0.18

ClinPred

0.18

GERP RS

3.4

Varity_R

0.075

gMVP

0.18

Mutation Taster

=89/11

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

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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