Genetic Variant PAX8:c.778-119C>A (chr2-113236840-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003466.4(PAX8):c.778-119C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,129,780 control chromosomes in the GnomAD database, including 139,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16170 hom., cov: 32)

Exomes 𝑓: 0.50 ( 123811 hom. )

Consequence

PAX8
NM_003466.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.50

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-113236840-G-T is Benign according to our data. Variant chr2-113236840-G-T is described in ClinVar as [Benign]. Clinvar id is 1265957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX8	NM_003466.4 link	c.778-119C>A		intron_variant	Intron 7 of 11	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.778-119C>A		intron_variant	Intron 7 of 11	1	NM_003466.4	ENSP00000395498.3		Q06710-1

Frequencies

GnomAD3 genomes

AF:

0.450

AC:

68331

AN:

151866

Hom.:

16172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.304

Gnomad AMI

AF:

0.383

Gnomad AMR

AF:

0.534

Gnomad ASJ

AF:

0.559

Gnomad EAS

AF:

0.652

Gnomad SAS

AF:

0.513

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.624

Gnomad NFE

AF:

0.501

Gnomad OTH

AF:

0.490

GnomAD4 exome

AF:

0.498

AC:

486471

AN:

977796

Hom.:

123811

Cov.:

AF XY:

0.499

AC XY:

241764

AN XY:

484736

show subpopulations

Gnomad4 AFR exome

AF:

0.297

Gnomad4 AMR exome

AF:

0.566

Gnomad4 ASJ exome

AF:

0.584

Gnomad4 EAS exome

AF:

0.649

Gnomad4 SAS exome

AF:

0.521

Gnomad4 FIN exome

AF:

0.414

Gnomad4 NFE exome

AF:

0.494

Gnomad4 OTH exome

AF:

0.504

GnomAD4 genome

AF:

0.450

AC:

68359

AN:

151984

Hom.:

16170

Cov.:

AF XY:

0.450

AC XY:

33409

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.304

Gnomad4 AMR

AF:

0.535

Gnomad4 ASJ

AF:

0.559

Gnomad4 EAS

AF:

0.652

Gnomad4 SAS

AF:

0.513

Gnomad4 FIN

AF:

0.399

Gnomad4 NFE

AF:

0.501

Gnomad4 OTH

AF:

0.491

Alfa

AF:

0.495

Hom.:

24207

Bravo

AF:

0.456

Asia WGS

AF:

0.529

AC:

1842

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.50

DANN

Benign

0.68

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

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