14-36661872-G-A

Variant names:

• chr14-36661872-G-A
• rs533579629
• NM_001372076.1:c.-218G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001372076.1(PAX9):​c.-218G>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 0.0000103 in 486,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PAX9 NM_001372076.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BS2: High AC in GnomAdExome4 at 5 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.-218G>A		5_prime_UTR	Exon 1 of 4	NP_001359005.1	P55771
	PAX9	NM_006194.4		c.-218G>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.-218G>A		5_prime_UTR	Exon 1 of 4	ENSP00000355245.6	P55771
	PAX9	ENST00000402703.6	TSL:5	c.-218G>A		5_prime_UTR	Exon 2 of 5	ENSP00000384817.2	P55771
	PAX9	ENST00000555639.2	TSL:5	c.-79-139G>A		intron	N/A	ENSP00000501203.1	A0A669KBA7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 5 AN: 486462 Hom.: 0 Cov.: 5 AF XY: 0.0000155 AC XY: 4 AN XY: 257846

African (AFR) AF: 0.00 AC: 0 AN: 13584

American (AMR) AF: 0.00 AC: 0 AN: 25816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15046

East Asian (EAS) AF: 0.00 AC: 0 AN: 30886

South Asian (SAS) AF: 0.0000200 AC: 1 AN: 49942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2074

European-Non Finnish (NFE) AF: 0.00000693 AC: 2 AN: 288700

Other (OTH) AF: 0.0000732 AC: 2 AN: 27308

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-0.28
CADD	Benign	22
DANN	Benign	0.91
PhyloP100		3.0
PromoterAI		-0.049	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs533579629; hg19: chr14-37131077;