14-36666548-G-C

Variant names:

• chr14-36666548-G-C
• rs4904210
• NM_001372076.1:c.718G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001372076.1(PAX9):​c.718G>C​(p.Ala240Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,585,086 control chromosomes in the GnomAD database, including 110,759 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A240V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.33 (8845 hom., cov: 35)
  • Exomes 𝑓: 0.38 (101914 hom.)
• Consequence: PAX9 NM_001372076.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.06
• Publications: 54 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002592355).
• BP6: Variant 14-36666548-G-C is Benign according to our data. Variant chr14-36666548-G-C is described in ClinVar as Benign. ClinVar VariationId is 259937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372076.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX9	NM_001372076.1	MANE Select	c.718G>C	p.Ala240Pro	missense	Exon 3 of 4	NP_001359005.1
	PAX9	NM_006194.4		c.718G>C	p.Ala240Pro	missense	Exon 4 of 5	NP_006185.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX9	ENST00000361487.7	TSL:1 MANE Select	c.718G>C	p.Ala240Pro	missense	Exon 3 of 4	ENSP00000355245.6
	PAX9	ENST00000402703.6	TSL:5	c.718G>C	p.Ala240Pro	missense	Exon 4 of 5	ENSP00000384817.2
	PAX9	ENST00000554201.1	TSL:2	n.1037G>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50650 AN: 152118 Hom.: 8844 Cov.: 35

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.364

GnomAD2 exomes AF: 0.361 AC: 72287 AN: 200266 AF XY: 0.369

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.376 AC: 538089 AN: 1432850 Hom.: 101914 Cov.: 54 AF XY: 0.378 AC XY: 268054 AN XY: 709942

African (AFR) AF: 0.235 AC: 7736 AN: 32912

American (AMR) AF: 0.261 AC: 10641 AN: 40798

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 10984 AN: 25564

East Asian (EAS) AF: 0.455 AC: 17381 AN: 38178

South Asian (SAS) AF: 0.403 AC: 33026 AN: 82006

European-Finnish (FIN) AF: 0.327 AC: 16645 AN: 50944

Middle Eastern (MID) AF: 0.384 AC: 2171 AN: 5658

European-Non Finnish (NFE) AF: 0.380 AC: 417293 AN: 1097518

Other (OTH) AF: 0.375 AC: 22212 AN: 59272

GnomAD4 genome AF: 0.333 AC: 50672 AN: 152236 Hom.: 8845 Cov.: 35 AF XY: 0.333 AC XY: 24808 AN XY: 74430

African (AFR) AF: 0.240 AC: 9969 AN: 41566

American (AMR) AF: 0.292 AC: 4474 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1512 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2318 AN: 5136

South Asian (SAS) AF: 0.419 AC: 2022 AN: 4830

European-Finnish (FIN) AF: 0.326 AC: 3460 AN: 10616

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25657 AN: 67992

Other (OTH) AF: 0.363 AC: 767 AN: 2114

Alfa AF: 0.369 Hom.: 3363

Bravo AF: 0.326

TwinsUK AF: 0.380 AC: 1410

ALSPAC AF: 0.382 AC: 1473

ESP6500AA AF: 0.228 AC: 995

ESP6500EA AF: 0.362 AC: 3097

ExAC AF: 0.332 AC: 39339

Asia WGS AF: 0.416 AC: 1448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tooth agenesis, selective, 3 Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Oct 27, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Feb 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30256498, 29023497, 24238416, 27884173, 20077892, 19641755, 24222224, 20660504, 21530942, 21111400)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypodontia Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Benign	0.060	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.36
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.42
gMVP		0.42
Mutation Taster		=91/9	polymorphism (auto)

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: rs4904210; hg19: chr14-37135753; COSMIC: COSV64061253; COSMIC: COSV64061253;