2-113216224-T-C

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.*2309A>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 0.763 in 230,346 control chromosomes in the GnomAD database, including 67,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (43537 hom., cov: 31)
  • Exomes 𝑓: 0.78 (23803 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38

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=-0.88).
• BP6: Variant 2-113216224-T-C is Benign according to our data. Variant chr2-113216224-T-C is described in ClinVar as [Benign]. Clinvar id is 330858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX8	NM_003466.4	c.*2309A>G		3_prime_UTR_variant	12/12	ENST00000429538.8
PAX8	NM_013952.4	c.*2386A>G		3_prime_UTR_variant	12/12
PAX8	NM_013953.4	c.*2386A>G		3_prime_UTR_variant	10/10
PAX8	NM_013992.4	c.*2386A>G		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.*2309A>G		3_prime_UTR_variant	12/12	1	NM_003466.4	P1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114820 AN: 151932 Hom.: 43509 Cov.: 31

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.739

GnomAD4 exome AF: 0.776 AC: 60771 AN: 78296 Hom.: 23803 Cov.: 0 AF XY: 0.778 AC XY: 28033 AN XY: 36050

Gnomad4 AFR exome AF: 0.734

Gnomad4 AMR exome AF: 0.747

Gnomad4 ASJ exome AF: 0.786

Gnomad4 EAS exome AF: 0.943

Gnomad4 SAS exome AF: 0.819

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.743

Gnomad4 OTH exome AF: 0.763

GnomAD4 genome AF: 0.756 AC: 114898 AN: 152050 Hom.: 43537 Cov.: 31 AF XY: 0.761 AC XY: 56575 AN XY: 74312

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.768

Gnomad4 ASJ AF: 0.782

Gnomad4 EAS AF: 0.935

Gnomad4 SAS AF: 0.807

Gnomad4 FIN AF: 0.777

Gnomad4 NFE AF: 0.740

Gnomad4 OTH AF: 0.741

Alfa AF: 0.745 Hom.: 8578

Bravo AF: 0.751

Asia WGS AF: 0.855 AC: 2971 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	-0.88
Cadd	Benign	0.044
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1077855; hg19: chr2-113973801;