chr2-113216055-G-A

Position:

• chr2-113216055-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003466.4(PAX8):​c.*2478C>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 0.449 in 221,038 control chromosomes in the GnomAD database, including 23,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (14827 hom., cov: 32)
  • Exomes 𝑓: 0.50 (8959 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.25

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-113216055-G-A is Benign according to our data. Variant chr2-113216055-G-A is described in ClinVar as [Benign]. Clinvar id is 330853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX8	NM_003466.4	c.*2478C>T		3_prime_UTR_variant	12/12	ENST00000429538.8
PAX8	NM_013952.4	c.*2555C>T		3_prime_UTR_variant	12/12
PAX8	NM_013953.4	c.*2555C>T		3_prime_UTR_variant	10/10
PAX8	NM_013992.4	c.*2555C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.*2478C>T		3_prime_UTR_variant	12/12	1	NM_003466.4	P1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64515 AN: 151894 Hom.: 14835 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.502 AC: 34647 AN: 69026 Hom.: 8959 Cov.: 0 AF XY: 0.503 AC XY: 16010 AN XY: 31846

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.594

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.531

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.488

GnomAD4 genome AF: 0.424 AC: 64518 AN: 152012 Hom.: 14827 Cov.: 32 AF XY: 0.428 AC XY: 31821 AN XY: 74316

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.524

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.467

Alfa AF: 0.473 Hom.: 6812

Bravo AF: 0.427

Asia WGS AF: 0.519 AC: 1807 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.85
CADD	Benign	0.34
DANN	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs2019137; hg19: chr2-113973632;