rs28933972

Positions:

• chr14-36662968-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000361487.7(PAX9):​c.76C>T​(p.Arg26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAX9 ENST00000361487.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a region_of_interest PAI subdomain (size 56) in uniprot entity PAX9_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000361487.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 14-36662968-C-T is Pathogenic according to our data. Variant chr14-36662968-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13774.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX9	NM_001372076.1	c.76C>T	p.Arg26Trp	missense_variant	2/4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4	c.76C>T	p.Arg26Trp	missense_variant	3/5		NP_006185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX9	ENST00000361487.7	c.76C>T	p.Arg26Trp	missense_variant	2/4	1	NM_001372076.1	ENSP00000355245	P1
PAX9	ENST00000402703.6	c.76C>T	p.Arg26Trp	missense_variant	3/5	5		ENSP00000384817	P1
PAX9	ENST00000555639.2	c.76C>T	p.Arg26Trp	missense_variant	3/3	5		ENSP00000501203
PAX9	ENST00000554201.1	n.395C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461210 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Partial congenital absence of teeth Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX9 protein function. ClinVar contains an entry for this variant (Variation ID: 13774). This missense change has been observed in individual(s) with oligodontia (PMID: 14571272, 28910570). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 26 of the PAX9 protein (p.Arg26Trp). -

Tooth agenesis, selective, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.97		Loss of MoRF binding (P = 0.1127);Loss of MoRF binding (P = 0.1127);
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs28933972; hg19: chr14-37132173; COSMIC: COSV64062712; COSMIC: COSV64062712;