chr14-36662951-C-T

Variant names:

• chr14-36662951-C-T
• rs1555316697
• NM_001372076.1:c.59C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001372076.1(PAX9):​c.59C>T​(p.Pro20Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX9 NM_001372076.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001372076.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 14-36662951-C-T is Pathogenic according to our data. Variant chr14-36662951-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375454.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX9	NM_001372076.1	c.59C>T	p.Pro20Leu	missense_variant	Exon 2 of 4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4	c.59C>T	p.Pro20Leu	missense_variant	Exon 3 of 5		NP_006185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX9	ENST00000361487.7	c.59C>T	p.Pro20Leu	missense_variant	Exon 2 of 4	1	NM_001372076.1	ENSP00000355245.6
PAX9	ENST00000402703.6	c.59C>T	p.Pro20Leu	missense_variant	Exon 3 of 5	5		ENSP00000384817.2
PAX9	ENST00000555639.2	c.59C>T	p.Pro20Leu	missense_variant	Exon 3 of 3	5		ENSP00000501203.1
PAX9	ENST00000554201.1	n.378C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Tooth agenesis, selective, 3 Pathogenic:2

-

Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2017

Maesawa Lab, Iwate Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant co-segregates with tooth agenesis in a family (3 affected, 1 unaffected). The Polyphen-2 score is 1.0 (probably damaging). In vitro experiment confirmed a functional defect of the variant protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.7	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.91		Gain of MoRF binding (P = 0.0648);Gain of MoRF binding (P = 0.0648);
MVP		0.97
MPC		3.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.88
Mutation Taster		=188/112	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555316697; hg19: chr14-37132156; COSMIC: COSV105277059; COSMIC: COSV105277059;