2-113216340-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003466.4(PAX8):c.*2193G>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 0.000246 in 231,898 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.888

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152260) while in subpopulation AMR AF= 0.000784 (12/15302). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX8	NM_003466.4	c.*2193G>A		3_prime_UTR_variant	12/12	ENST00000429538.8
PAX8	NM_013952.4	c.*2270G>A		3_prime_UTR_variant	12/12
PAX8	NM_013953.4	c.*2270G>A		3_prime_UTR_variant	10/10
PAX8	NM_013992.4	c.*2270G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.*2193G>A		3_prime_UTR_variant	12/12	1	NM_003466.4	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152142 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000301 AC: 24 AN: 79638 Hom.: 0 Cov.: 0 AF XY: 0.000355 AC XY: 13 AN XY: 36614

Gnomad4 AFR exome AF: 0.000527

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000890

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.000601

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 2 Uncertain:1

Uncertain significance, 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.1
Dann	Benign	0.36

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: rs148816725; hg19: chr2-113973917;