rs3188996

Positions:

chr2-113235496-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003466.4(PAX8):c.985T>C(p.Phe329Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0247 in 1,613,868 control chromosomes in the GnomAD database, including 614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.016 ( 37 hom., cov: 32)

Exomes 𝑓: 0.026 ( 577 hom. )

Consequence

PAX8
NM_003466.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.92

Variant links:

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 links:

PAX8-AS1 (HGNC:):

PAX8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008379161).

BP6

Variant 2-113235496-A-G is Benign according to our data. Variant chr2-113235496-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 13782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-113235496-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0159 (2417/152312) while in subpopulation NFE AF= 0.0278 (1893/68018). AF 95% confidence interval is 0.0268. There are 37 homozygotes in gnomad4. There are 1107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX8	NM_003466.4 linkuse as main transcript	c.985T>C	p.Phe329Leu	missense_variant	9/12	ENST00000429538.8	NP_003457.1	Q06710-1R9W7C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX8	ENST00000429538.8 linkuse as main transcript	c.985T>C	p.Phe329Leu	missense_variant	9/12	1	NM_003466.4	ENSP00000395498.3		Q06710-1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2416

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00516

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0278

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0164

AC:

4064

AN:

248264

Hom.:

AF XY:

0.0161

AC XY:

2173

AN XY:

134964

show subpopulations

Gnomad AFR exome

AF:

0.00448

Gnomad AMR exome

AF:

0.00557

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00775

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0278

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0257

AC:

37524

AN:

1461556

Hom.:

577

Cov.:

AF XY:

0.0248

AC XY:

18046

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.00400

Gnomad4 AMR exome

AF:

0.00544

Gnomad4 ASJ exome

AF:

0.00578

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00784

Gnomad4 FIN exome

AF:

0.0140

Gnomad4 NFE exome

AF:

0.0308

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0159

AC:

2417

AN:

152312

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1107

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00515

Gnomad4 AMR

AF:

0.00594

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.0123

Gnomad4 NFE

AF:

0.0278

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0243

Hom.:

Bravo

AF:

0.0155

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.00418

AC:

ESP6500EA

AF:

0.0260

AC:

215

ExAC

AF:

0.0176

AC:

2127

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0260

EpiControl

AF:

0.0263

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hypothyroidism, congenital, nongoitrous, 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 20, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PAX8: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PAX8 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 17, 1997

- -

PAX8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.69

T;.

MetaRNN

Benign

0.0084

T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

0.42

N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.1

.;N

REVEL

Uncertain

0.38

Sift

Benign

0.44

.;T

Sift4G

Benign

0.67

T;T

Polyphen

0.92

P;P

Vest4

0.28

MutPred

0.10

Loss of glycosylation at S326 (P = 0.0872);Loss of glycosylation at S326 (P = 0.0872);

MPC

0.061

ClinPred

0.10

GERP RS

5.6

Varity_R

0.28

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over