rs61754301

Positions:

chr14-36663501-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The ENST00000361487.7(PAX9):c.609C>T(p.Gly203=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,612,952 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

PAX9
ENST00000361487.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.119

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 14-36663501-C-T is Benign according to our data. Variant chr14-36663501-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456653.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.

BP7

Synonymous conserved (PhyloP=0.119 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00137 (209/152320) while in subpopulation AMR AF= 0.00242 (37/15310). AF 95% confidence interval is 0.0018. There are 0 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX9	NM_001372076.1 linkuse as main transcript	c.609C>T	p.Gly203=	synonymous_variant	2/4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4 linkuse as main transcript	c.609C>T	p.Gly203=	synonymous_variant	3/5		NP_006185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAX9	ENST00000361487.7 linkuse as main transcript	c.609C>T	p.Gly203=	synonymous_variant	2/4	1	NM_001372076.1	ENSP00000355245	P1
PAX9	ENST00000402703.6 linkuse as main transcript	c.609C>T	p.Gly203=	synonymous_variant	3/5	5		ENSP00000384817	P1
PAX9	ENST00000554201.1 linkuse as main transcript	n.928C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00125

AC:

300

AN:

240668

Hom.:

AF XY:

0.00120

AC XY:

158

AN XY:

131506

show subpopulations

Gnomad AFR exome

AF:

0.000527

Gnomad AMR exome

AF:

0.000929

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00310

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.00251

GnomAD4 exome

AF:

0.00187

AC:

2736

AN:

1460632

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1291

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00336

Gnomad4 NFE exome

AF:

0.00214

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152320

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00181

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.00145

EpiCase

AF:

0.00174

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tooth agenesis, selective, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Partial congenital absence of teeth

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2022

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

PAX9: BP4, BP7 -

PAX9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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