2-113216387-T-C

Position:

• chr2-113216387-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003466.4(PAX8):​c.*2146A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 231,298 control chromosomes in the GnomAD database, including 25,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14808 hom., cov: 32)
  • Exomes 𝑓: 0.51 (10468 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.387

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-113216387-T-C is Benign according to our data. Variant chr2-113216387-T-C is described in ClinVar as [Benign]. Clinvar id is 330861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.*2146A>G		3_prime_UTR_variant	12/12	ENST00000429538.8
PAX8	NM_013952.4	c.*2223A>G		3_prime_UTR_variant	12/12
PAX8	NM_013953.4	c.*2223A>G		3_prime_UTR_variant	10/10
PAX8	NM_013992.4	c.*2223A>G		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.*2146A>G		3_prime_UTR_variant	12/12	1	NM_003466.4	P1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64431 AN: 151930 Hom.: 14816 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.507 AC: 40158 AN: 79250 Hom.: 10468 Cov.: 0 AF XY: 0.508 AC XY: 18528 AN XY: 36486

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.594

Gnomad4 EAS exome AF: 0.629

Gnomad4 SAS exome AF: 0.532

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.489

Gnomad4 OTH exome AF: 0.492

GnomAD4 genome AF: 0.424 AC: 64434 AN: 152048 Hom.: 14808 Cov.: 32 AF XY: 0.428 AC XY: 31780 AN XY: 74322

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.467

Alfa AF: 0.481 Hom.: 17621

Bravo AF: 0.427

Asia WGS AF: 0.520 AC: 1810 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 2 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.80
DANN	Benign	0.75

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: rs895412; hg19: chr2-113973964;