14-36661904-C-A

Variant names:

• chr14-36661904-C-A
• rs886050489
• NM_001372076.1:c.-186C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001372076.1(PAX9):​c.-186C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 716,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (2 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: PAX9 NM_001372076.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 0 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000571 (87/152346) while in subpopulation AFR AF = 0.00202 (84/41574). AF 95% confidence interval is 0.00167. There are 2 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 87 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX9	NM_001372076.1	MANE Select	c.-186C>A		5_prime_UTR	Exon 1 of 4	NP_001359005.1	P55771
	PAX9	NM_006194.4		c.-186C>A		5_prime_UTR	Exon 2 of 5	NP_006185.1	P55771

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX9	ENST00000361487.7	TSL:1 MANE Select	c.-186C>A		5_prime_UTR	Exon 1 of 4	ENSP00000355245.6	P55771
	PAX9	ENST00000402703.6	TSL:5	c.-186C>A		5_prime_UTR	Exon 2 of 5	ENSP00000384817.2	P55771
	PAX9	ENST00000555639.2	TSL:5	c.-79-107C>A		intron	N/A	ENSP00000501203.1	A0A669KBA7

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152228 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000638 AC: 36 AN: 564012 Hom.: 0 Cov.: 7 AF XY: 0.0000700 AC XY: 21 AN XY: 300144

African (AFR) AF: 0.00174 AC: 27 AN: 15528

American (AMR) AF: 0.0000971 AC: 3 AN: 30908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17274

East Asian (EAS) AF: 0.00 AC: 0 AN: 31870

South Asian (SAS) AF: 0.0000180 AC: 1 AN: 55594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 339244

Other (OTH) AF: 0.000165 AC: 5 AN: 30288

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74496

African (AFR) AF: 0.00202 AC: 84 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000586

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Tooth agenesis, selective, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		1.9
PromoterAI		-0.059	Neutral

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: rs886050489; hg19: chr14-37131109;