rs61734510

chr14-36663408-G-Achr14-36663408-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001372076.1(PAX9):c.516G>A(p.Lys172=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,613,250 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (86 hom.)
• Consequence: PAX9 NM_001372076.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-36663408-G-A is Benign according to our data. Variant chr14-36663408-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 313168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00937 (1427/152294) while in subpopulation AFR AF= 0.0145 (603/41570). AF 95% confidence interval is 0.0135. There are 13 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX9	NM_001372076.1	c.516G>A	p.Lys172=	synonymous_variant	2/4	ENST00000361487.7
PAX9	NM_006194.4	c.516G>A	p.Lys172=	synonymous_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX9	ENST00000361487.7	c.516G>A	p.Lys172=	synonymous_variant	2/4	1	NM_001372076.1	P1
PAX9	ENST00000402703.6	c.516G>A	p.Lys172=	synonymous_variant	3/5	5		P1
PAX9	ENST00000554201.1	n.835G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1429 AN: 152176 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00892

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00675 AC: 1667 AN: 247088 Hom.: 16 AF XY: 0.00687 AC XY: 923 AN XY: 134256

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00906

Gnomad FIN exome AF: 0.00390

Gnomad NFE exome AF: 0.00788

Gnomad OTH exome AF: 0.00924

GnomAD4 exome AF: 0.00872 AC: 12735 AN: 1460956 Hom.: 86 Cov.: 37 AF XY: 0.00860 AC XY: 6252 AN XY: 726784

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00910

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.00931

Gnomad4 OTH exome AF: 0.00797

GnomAD4 genome AF: 0.00937 AC: 1427 AN: 152294 Hom.: 13 Cov.: 33 AF XY: 0.00848 AC XY: 631 AN XY: 74448

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.00633

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00892

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00767 Hom.: 2

Bravo AF: 0.00972

EpiCase AF: 0.00812

EpiControl AF: 0.00788

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Partial congenital absence of teeth Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Tooth agenesis, selective, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

PAX9: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	11
Dann	Benign	0.95

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

Other links and lift over

dbSNP: rs61734510; hg19: chr14-37132613;