2-113217489-T-G

Position:

• chr2-113217489-T-G

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.*1044A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 229,214 control chromosomes in the GnomAD database, including 8,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6369 hom., cov: 33)
  • Exomes 𝑓: 0.20 (1729 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.432

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-113217489-T-G is Benign according to our data. Variant chr2-113217489-T-G is described in ClinVar as [Benign]. Clinvar id is 330868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX8	NM_003466.4	c.*1044A>C		3_prime_UTR_variant	12/12	ENST00000429538.8	NP_003457.1
PAX8	NM_013952.4	c.*1121A>C		3_prime_UTR_variant	12/12		NP_039246.1
PAX8	NM_013953.4	c.*1121A>C		3_prime_UTR_variant	10/10		NP_039247.1
PAX8	NM_013992.4	c.*1121A>C		3_prime_UTR_variant	9/9		NP_054698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX8	ENST00000429538	c.*1044A>C		3_prime_UTR_variant	12/12	1	NM_003466.4	ENSP00000395498.3

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40913 AN: 151668 Hom.: 6358 Cov.: 33

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.196 AC: 15141 AN: 77430 Hom.: 1729 Cov.: 0 AF XY: 0.197 AC XY: 7070 AN XY: 35832

Gnomad4 AFR exome AF: 0.408

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.0724

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.219

GnomAD4 genome AF: 0.270 AC: 40965 AN: 151784 Hom.: 6369 Cov.: 33 AF XY: 0.267 AC XY: 19776 AN XY: 74178

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.225

Alfa AF: 0.204 Hom.: 3497

Bravo AF: 0.270

Asia WGS AF: 0.163 AC: 569 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 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. -

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	-0.66
CADD	Benign	6.9
DANN	Benign	0.88

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: rs1478; hg19: chr2-113975066; COSMIC: COSV54511219; COSMIC: COSV54511219;