Genetic Variant PAX3:c.1420+125_1420+126dupTT (chr2-222201817-C-CAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_181458.4(PAX3):c.1420+125_1420+126dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,437,694 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 24)

Exomes 𝑓: 0.0067 ( 0 hom. )

Consequence

PAX3
NM_181458.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.474

Publications

3 publications found

Variant links:

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

PAX3 Gene-Disease associations (from GenCC):

craniofacial-deafness-hand syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Waardenburg syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Waardenburg syndrome type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Waardenburg syndrome type 3
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

PAX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00309 (393/127388) while in subpopulation EAS AF = 0.00709 (32/4516). AF 95% confidence interval is 0.00606. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.1420+125_1420+126dupTT		intron_variant	Intron 8 of 8	ENST00000392070.7	NP_852123.1	P23760-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 link	c.1420+125_1420+126dupTT		intron_variant	Intron 8 of 8	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

392

AN:

127332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00680

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000649

Gnomad EAS

AF:

0.00685

Gnomad SAS

AF:

0.00491

Gnomad FIN

AF:

0.000903

Gnomad MID

AF:

0.00368

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.00174

GnomAD4 exome

AF:

0.00669

AC:

8767

AN:

1310306

Hom.:

Cov.:

AF XY:

0.00696

AC XY:

4517

AN XY:

649310

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00733

AC:

215

AN:

29334

American (AMR)

AF:

0.00475

AC:

160

AN:

33666

Ashkenazi Jewish (ASJ)

AF:

0.00967

AC:

222

AN:

22952

East Asian (EAS)

AF:

0.00945

AC:

342

AN:

36208

South Asian (SAS)

AF:

0.0107

AC:

788

AN:

73814

European-Finnish (FIN)

AF:

0.00795

AC:

343

AN:

43120

Middle Eastern (MID)

AF:

0.00967

AC:

AN:

3928

European-Non Finnish (NFE)

AF:

0.00617

AC:

6248

AN:

1012852

Other (OTH)

AF:

0.00755

AC:

411

AN:

54432

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

868

1736

2605

3473

4341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00309

AC:

393

AN:

127388

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

214

AN XY:

61182

show subpopulations

African (AFR)

AF:

0.00678

AC:

231

AN:

34068

American (AMR)

AF:

0.00170

AC:

AN:

12344

Ashkenazi Jewish (ASJ)

AF:

0.000649

AC:

AN:

3084

East Asian (EAS)

AF:

0.00709

AC:

AN:

4516

South Asian (SAS)

AF:

0.00493

AC:

AN:

4058

European-Finnish (FIN)

AF:

0.000903

AC:

AN:

7754

Middle Eastern (MID)

AF:

0.00407

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

58808

Other (OTH)

AF:

0.00172

AC:

AN:

1740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000145

Hom.:

110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-222201817-CAAAAAAA-CAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over