NM_001372076.1:c.*818C>T

Variant names:

• chr14-36677270-C-T
• rs11847165
• NM_001372076.1:c.*818C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001372076.1(PAX9):​c.*818C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 151,858 control chromosomes in the GnomAD database, including 3,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3021 hom., cov: 32)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: PAX9 NM_001372076.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.862
• Publications: 10 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: G2P, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-36677270-C-T is Benign according to our data. Variant chr14-36677270-C-T is described in ClinVar as Benign. ClinVar VariationId is 313183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX9	NM_001372076.1	c.*818C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000361487.7	NP_001359005.1
PAX9	NM_006194.4	c.*818C>T		3_prime_UTR_variant	Exon 5 of 5		NP_006185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX9	ENST00000361487.7	c.*818C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_001372076.1	ENSP00000355245.6
PAX9	ENST00000402703.6	c.*818C>T		3_prime_UTR_variant	Exon 5 of 5	5		ENSP00000384817.2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28762 AN: 151660 Hom.: 3014 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.131 AC: 11 AN: 84 Hom.: 1 Cov.: 0 AF XY: 0.138 AC XY: 8 AN XY: 58

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0972 AC: 7 AN: 72

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.190 AC: 28800 AN: 151774 Hom.: 3021 Cov.: 32 AF XY: 0.196 AC XY: 14558 AN XY: 74146

African (AFR) AF: 0.211 AC: 8713 AN: 41336

American (AMR) AF: 0.320 AC: 4868 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3472

East Asian (EAS) AF: 0.209 AC: 1075 AN: 5154

South Asian (SAS) AF: 0.146 AC: 702 AN: 4796

European-Finnish (FIN) AF: 0.234 AC: 2457 AN: 10522

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.145 AC: 9868 AN: 67966

Other (OTH) AF: 0.189 AC: 398 AN: 2108

Alfa AF: 0.170 Hom.: 3162

Bravo AF: 0.198

Asia WGS AF: 0.223 AC: 776 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tooth agenesis, selective, 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

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: rs11847165; hg19: chr14-37146475;