Genetic Variant PAX8:c.*2276G>A (chr2-113216257-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003466.4(PAX8):c.*2276G>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 0.0016 in 231,208 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 0 hom. )

Consequence

PAX8
NM_003466.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.14

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 2-113216257-C-T is Benign according to our data. Variant chr2-113216257-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 894354.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00139 (211/152280) while in subpopulation EAS AF = 0.00676 (35/5180). AF 95% confidence interval is 0.00499. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 211 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003466.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PAX8	NM_003466.4	MANE Select	c.*2276G>A	3_prime_UTR	Exon 12 of 12	NP_003457.1	Q06710-1
PAX8	NM_013952.4		c.*2353G>A	3_prime_UTR	Exon 12 of 12	NP_039246.1	Q06710-3
PAX8	NM_013953.4		c.*2353G>A	3_prime_UTR	Exon 10 of 10	NP_039247.1	Q06710-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PAX8	ENST00000429538.8	TSL:1 MANE Select	c.*2276G>A	3_prime_UTR	Exon 12 of 12	ENSP00000395498.3	Q06710-1
PAX8	ENST00000263334.9	TSL:1	c.*2276G>A	3_prime_UTR	Exon 12 of 12	ENSP00000263334.6	Q06710-1
PAX8	ENST00000348715.9	TSL:1	c.*2353G>A	3_prime_UTR	Exon 12 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

211

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00674

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00200

AC:

158

AN:

78928

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

AN XY:

36338

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

3780

American (AMR)

AF:

0.00

AC:

AN:

2414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4984

East Asian (EAS)

AF:

0.00422

AC:

AN:

11126

South Asian (SAS)

AF:

0.00

AC:

AN:

684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

482

European-Non Finnish (NFE)

AF:

0.00191

AC:

AN:

48784

Other (OTH)

AF:

0.00242

AC:

AN:

6616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00139

AC:

211

AN:

152280

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41552

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00676

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00225

AC:

153

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00122

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypothyroidism, congenital, nongoitrous, 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.66

(source)

DANN

Benign

0.60

PhyloP100

-1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over