14-36657839-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000555107.1(ENSG00000258661):n.258+705G>C variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,094 control chromosomes in the GnomAD database, including 10,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10671 hom., cov: 32)
  • Exomes 𝑓: 0.32 (15 hom.)
• Consequence: ENST00000555107.1 intron, non_coding_transcript
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05

Genes affected

(HGNC:):

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 -10 ACMG points.

• BP6: Variant 14-36657839-C-G is Benign according to our data. Variant chr14-36657839-C-G is described in ClinVar as [Benign]. Clinvar id is 313155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC105370455	XR_943758.3	n.206+705G>C		intron_variant, non_coding_transcript_variant
PAX9	NM_006194.4	c.-455C>G		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000555107.1	n.258+705G>C		intron_variant, non_coding_transcript_variant		3
PAX9	ENST00000402703.6	c.-455C>G		5_prime_UTR_variant	1/5	5		P1
PAX9	ENST00000555639.2	c.-134C>G		5_prime_UTR_variant	1/3	5
PAX9	ENST00000553267.4	n.272C>G		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56439 AN: 151806 Hom.: 10657 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.324 AC: 55 AN: 170 Hom.: 15 Cov.: 0 AF XY: 0.341 AC XY: 45 AN XY: 132

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.250

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.372 AC: 56490 AN: 151924 Hom.: 10671 Cov.: 32 AF XY: 0.372 AC XY: 27623 AN XY: 74266

Gnomad4 AFR AF: 0.395

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.414

Gnomad4 FIN AF: 0.310

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.392

Alfa AF: 0.364 Hom.: 1322

Bravo AF: 0.373

Asia WGS AF: 0.424 AC: 1476 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tooth agenesis, selective, 3 Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	6.7
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4904155; hg19: chr14-37127044;