rs3188996

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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

Publications

16 publications found

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:49271): (PAX8 antisense RNA 1)

PAX8-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX8	NM_003466.4 link	c.985T>C	p.Phe329Leu	missense_variant	Exon 9 of 12	ENST00000429538.8	NP_003457.1	Q06710-1R9W7C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX8	ENST00000429538.8 link	c.985T>C	p.Phe329Leu	missense_variant	Exon 9 of 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

GnomAD2 exomes

AF:

0.0164

AC:

4064

AN:

248264

AF XY:

0.0161

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 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

African (AFR)

AF:

0.00400

AC:

134

AN:

33478

American (AMR)

AF:

0.00544

AC:

243

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00578

AC:

151

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00784

AC:

676

AN:

86232

European-Finnish (FIN)

AF:

0.0140

AC:

745

AN:

53378

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0308

AC:

34242

AN:

1111794

Other (OTH)

AF:

0.0216

AC:

1304

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1973

3945

5918

7890

9863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0159

AC:

2417

AN:

152312

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1107

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00515

AC:

214

AN:

41584

American (AMR)

AF:

0.00594

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00726

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0123

AC:

130

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0278

AC:

1893

AN:

68018

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0230

Hom.:

107

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypothyroidism, congenital, nongoitrous, 2

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PAX8: BS1, BS2 -

PAX8 POLYMORPHISM

Benign:1

Oct 17, 1997

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PAX8-related disorder

Benign:1

Dec 03, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

5.9

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

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.28

gMVP

0.49

Mutation Taster

=70/30

polymorphism (auto)

(source)

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

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rs3188996

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over