2-113216257-C-T

Position:

• chr2-113216257-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003466.4(PAX8):​c.*2276G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 231,208 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.14

Genes affected

PAX8 (HGNC:8622): (paired box 8) This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

PAX8-AS1 (HGNC:49271): (PAX8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-113216257-C-T is Benign according to our data. Variant chr2-113216257-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 894354.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00139 (211/152280) while in subpopulation EAS AF= 0.00676 (35/5180). AF 95% confidence interval is 0.00499. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX8	NM_003466.4	c.*2276G>A		3_prime_UTR_variant	12/12	ENST00000429538.8
PAX8	NM_013952.4	c.*2353G>A		3_prime_UTR_variant	12/12
PAX8	NM_013953.4	c.*2353G>A		3_prime_UTR_variant	10/10
PAX8	NM_013992.4	c.*2353G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.*2276G>A		3_prime_UTR_variant	12/12	1	NM_003466.4	P1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00200 AC: 158 AN: 78928 Hom.: 0 Cov.: 0 AF XY: 0.00173 AC XY: 63 AN XY: 36338

Gnomad4 AFR exome AF: 0.000529

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00422

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00191

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74460

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00676

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

PAX8: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs189067014; hg19: chr2-113973834;