2-222202200-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181458.4(PAX3):c.1174-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,566,748 control chromosomes in the GnomAD database, including 14,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1207 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13028 hom. )

Consequence

PAX3
NM_181458.4 intron

Scores

Splicing: ADA: 0.0001188

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.14

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 2-222202200-C-G is Benign according to our data. Variant chr2-222202200-C-G is described in ClinVar as Benign. ClinVar VariationId is 226998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.1174-10G>C		intron_variant	Intron 7 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.1174-10G>C		intron_variant	Intron 7 of 8	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17619

AN:

152038

Hom.:

1208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0795

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0334

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.151

GnomAD2 exomes

AF:

0.108

AC:

20972

AN:

194398

AF XY:

0.106

show subpopulations

Gnomad AFR exome

AF:

0.0738

Gnomad AMR exome

AF:

0.0928

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.000280

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.130

AC:

184477

AN:

1414592

Hom.:

13028

Cov.:

AF XY:

0.128

AC XY:

89666

AN XY:

701240

show subpopulations

African (AFR)

AF:

0.0809

AC:

2620

AN:

32372

American (AMR)

AF:

0.0977

AC:

3841

AN:

39308

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

4901

AN:

25494

East Asian (EAS)

AF:

0.000158

AC:

AN:

37940

South Asian (SAS)

AF:

0.0372

AC:

3060

AN:

82178

European-Finnish (FIN)

AF:

0.115

AC:

5918

AN:

51334

Middle Eastern (MID)

AF:

0.182

AC:

975

AN:

5352

European-Non Finnish (NFE)

AF:

0.144

AC:

155378

AN:

1081980

Other (OTH)

AF:

0.133

AC:

7778

AN:

58634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

7267

14534

21802

29069

36336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5456

10912

16368

21824

27280

<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:

0.116

AC:

17609

AN:

152156

Hom.:

1207

Cov.:

AF XY:

0.114

AC XY:

8505

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0792

AC:

3289

AN:

41506

American (AMR)

AF:

0.145

AC:

2208

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

652

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0332

AC:

160

AN:

4820

European-Finnish (FIN)

AF:

0.118

AC:

1254

AN:

10594

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9629

AN:

68000

Other (OTH)

AF:

0.149

AC:

314

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

784

1568

2353

3137

3921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.0940

Hom.:

182

Bravo

AF:

0.117

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

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

1174-10G>C in intron 7C of PAX3: This variant is not expected to have clinical s ignificance because it has been identified in 14.6% (1259/8598) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2855268). -

Aug 03, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Craniofacial-deafness-hand syndrome

Benign:1

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. -

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

-0.69

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.0020

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