rs61754301

chr14-36663501-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001372076.1(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 NM_001372076.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.119

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 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=2}.
• 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 GnomAd at 209 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152202 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.00120 AC XY: 158 AN XY: 131506

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.: 3 Cov.: 37 AF XY: 0.00178 AC XY: 1291 AN XY: 726622

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.: 0 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74480

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.: 0

Bravo AF: 0.00145

EpiCase AF: 0.00174

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

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

Invitae

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, criteria provided, single submitter

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	11
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

Other links and lift over

dbSNP: rs61754301; hg19: chr14-37132706;