chr14-36666548-G-C

Position:

chr14-36666548-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8845 hom., cov: 35)

Exomes 𝑓: 0.38 ( 101914 hom. )

Consequence

PAX9
NM_001372076.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 259937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-36666548-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX9	NM_001372076.1 linkuse as main transcript	c.718G>C	p.Ala240Pro	missense_variant	3/4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4 linkuse as main transcript	c.718G>C	p.Ala240Pro	missense_variant	4/5		NP_006185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAX9	ENST00000361487.7 linkuse as main transcript	c.718G>C	p.Ala240Pro	missense_variant	3/4	1	NM_001372076.1	ENSP00000355245	P1
PAX9	ENST00000402703.6 linkuse as main transcript	c.718G>C	p.Ala240Pro	missense_variant	4/5	5		ENSP00000384817	P1
PAX9	ENST00000554201.1 linkuse as main transcript	n.1037G>C		non_coding_transcript_exon_variant	2/3	2
PAX9	ENST00000557107.1 linkuse as main transcript	n.559G>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50650

AN:

152118

Hom.:

8844

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.361

AC:

72287

AN:

200266

Hom.:

13277

AF XY:

0.369

AC XY:

39851

AN XY:

107990

show subpopulations

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 SAS exome

AF:

0.400

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.:

AF XY:

0.378

AC XY:

268054

AN XY:

709942

show subpopulations

Gnomad4 AFR exome

AF:

0.235

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.430

Gnomad4 EAS exome

AF:

0.455

Gnomad4 SAS exome

AF:

0.403

Gnomad4 FIN exome

AF:

0.327

Gnomad4 NFE exome

AF:

0.380

Gnomad4 OTH exome

AF:

0.375

GnomAD4 genome

AF:

0.333

AC:

50672

AN:

152236

Hom.:

8845

Cov.:

AF XY:

0.333

AC XY:

24808

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.240

Gnomad4 AMR

AF:

0.292

Gnomad4 ASJ

AF:

0.436

Gnomad4 EAS

AF:

0.451

Gnomad4 SAS

AF:

0.419

Gnomad4 FIN

AF:

0.326

Gnomad4 NFE

AF:

0.377

Gnomad4 OTH

AF:

0.363

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

LINK: link

Submissions by phenotype

Tooth agenesis, selective, 3

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 27, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	This variant is associated with the following publications: (PMID: 30256498, 29023497, 24238416, 27884173, 20077892, 19641755, 24222224, 20660504, 21530942, 21111400) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Partial congenital absence of teeth

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.63

T;.;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

0.97

P;P;P

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.060

T;T;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.12

MPC

0.36

ClinPred

0.014

GERP RS

3.4

Varity_R

0.42

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over