2-222297170-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_181458.4(PAX3):c.129T>C(p.Gly43Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 1,600,354 control chromosomes in the GnomAD database, including 589,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 56012 hom., cov: 36)

Exomes 𝑓: 0.86 ( 533051 hom. )

Consequence

PAX3
NM_181458.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.24

Publications

27 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 2-222297170-A-G is Benign according to our data. Variant chr2-222297170-A-G is described in ClinVar as Benign. ClinVar VariationId is 195432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.129T>C	p.Gly43Gly	synonymous_variant	Exon 2 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.129T>C	p.Gly43Gly	synonymous_variant	Exon 2 of 9	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.856

AC:

130250

AN:

152184

Hom.:

55961

Cov.:

show subpopulations

Gnomad AFR

AF:

0.837

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.912

Gnomad ASJ

AF:

0.924

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.953

Gnomad FIN

AF:

0.829

Gnomad MID

AF:

0.934

Gnomad NFE

AF:

0.839

Gnomad OTH

AF:

0.888

GnomAD2 exomes

AF:

0.884

AC:

197338

AN:

223172

AF XY:

0.886

show subpopulations

Gnomad AFR exome

AF:

0.836

Gnomad AMR exome

AF:

0.937

Gnomad ASJ exome

AF:

0.925

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.827

Gnomad NFE exome

AF:

0.841

Gnomad OTH exome

AF:

0.888

GnomAD4 exome

AF:

0.857

AC:

1241099

AN:

1448052

Hom.:

533051

Cov.:

AF XY:

0.860

AC XY:

618686

AN XY:

719310

show subpopulations

African (AFR)

AF:

0.836

AC:

27718

AN:

33140

American (AMR)

AF:

0.932

AC:

39700

AN:

42596

Ashkenazi Jewish (ASJ)

AF:

0.926

AC:

23918

AN:

25842

East Asian (EAS)

AF:

1.00

AC:

38867

AN:

38874

South Asian (SAS)

AF:

0.952

AC:

80254

AN:

84340

European-Finnish (FIN)

AF:

0.833

AC:

43430

AN:

52110

Middle Eastern (MID)

AF:

0.949

AC:

5449

AN:

5744

European-Non Finnish (NFE)

AF:

0.841

AC:

929546

AN:

1105648

Other (OTH)

AF:

0.874

AC:

52217

AN:

59758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

10465

20929

31394

41858

52323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21064

42128

63192

84256

105320

<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:

0.856

AC:

130358

AN:

152302

Hom.:

56012

Cov.:

AF XY:

0.858

AC XY:

63925

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.837

AC:

34793

AN:

41550

American (AMR)

AF:

0.912

AC:

13956

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.924

AC:

3208

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5170

AN:

5172

South Asian (SAS)

AF:

0.953

AC:

4602

AN:

4828

European-Finnish (FIN)

AF:

0.829

AC:

8803

AN:

10614

Middle Eastern (MID)

AF:

0.932

AC:

274

AN:

294

European-Non Finnish (NFE)

AF:

0.839

AC:

57103

AN:

68036

Other (OTH)

AF:

0.889

AC:

1881

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1007

2013

3020

4026

5033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.853

Hom.:

48652

Bravo

AF:

0.859

Asia WGS

AF:

0.969

AC:

3371

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 04, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly43Gly in exon 2 of PAX3: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 15.5% (682/4396) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12623857). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Craniofacial-deafness-hand syndrome

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Waardenburg syndrome type 3

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Waardenburg syndrome type 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Waardenburg syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

-0.78

CADD

Benign

2.4

(source)

DANN

Benign

0.61

PhyloP100

-2.2

Mutation Taster

=90/10

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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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