Genetic Variant PAX3:c.*372_*373dupGT (chr2-222201034-T-TAC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_181458.4(PAX3):c.*372_*373dupGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 793,502 control chromosomes in the GnomAD database, including 581 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 553 hom., cov: 31)

Exomes 𝑓: 0.0095 ( 28 hom. )

Consequence

PAX3
NM_181458.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.01

Publications

4 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.372_373dupGT		3_prime_UTR_variant	Exon 9 of 9	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.372_373dupGT		3_prime_UTR_variant	Exon 9 of 9	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.0512

AC:

7641

AN:

149178

Hom.:

554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0280

Gnomad ASJ

AF:

0.0304

Gnomad EAS

AF:

0.00255

Gnomad SAS

AF:

0.00235

Gnomad FIN

AF:

0.00312

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.00328

Gnomad OTH

AF:

0.0472

GnomAD4 exome

AF:

0.00946

AC:

6096

AN:

644230

Hom.:

Cov.:

AF XY:

0.00842

AC XY:

2805

AN XY:

333214

show subpopulations

African (AFR)

AF:

0.147

AC:

2472

AN:

16788

American (AMR)

AF:

0.0155

AC:

449

AN:

28894

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

458

AN:

16366

East Asian (EAS)

AF:

0.00190

AC:

AN:

29486

South Asian (SAS)

AF:

0.00227

AC:

115

AN:

50708

European-Finnish (FIN)

AF:

0.00402

AC:

150

AN:

37280

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

3902

European-Non Finnish (NFE)

AF:

0.00408

AC:

1751

AN:

428864

Other (OTH)

AF:

0.0188

AC:

601

AN:

31942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

243

486

729

972

1215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0513

AC:

7658

AN:

149272

Hom.:

553

Cov.:

AF XY:

0.0491

AC XY:

3573

AN XY:

72778

show subpopulations

African (AFR)

AF:

0.165

AC:

6765

AN:

40882

American (AMR)

AF:

0.0280

AC:

419

AN:

14966

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

104

AN:

3418

East Asian (EAS)

AF:

0.00236

AC:

AN:

5090

South Asian (SAS)

AF:

0.00214

AC:

AN:

4678

European-Finnish (FIN)

AF:

0.00312

AC:

AN:

9928

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00327

AC:

219

AN:

67040

Other (OTH)

AF:

0.0468

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

319

638

958

1277

1596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000743

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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chr2-222201034-T-TAC

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