rs12623857

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_181458.4(PAX3):c.129T>C(p.Gly43=) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 195432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-222297170-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PAX3	NM_181458.4 linkuse as main transcript	c.129T>C	p.Gly43=	synonymous_variant	2/9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 linkuse as main transcript	c.129T>C	p.Gly43=	synonymous_variant	2/9	1	NM_181458.4	ENSP00000375922	A1	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

GnomAD3 exomes

AF:

0.884

AC:

197338

AN:

223172

Hom.:

87545

AF XY:

0.886

AC XY:

107590

AN XY:

121476

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 SAS exome

AF:

0.955

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

Gnomad4 AFR exome

AF:

0.836

Gnomad4 AMR exome

AF:

0.932

Gnomad4 ASJ exome

AF:

0.926

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.952

Gnomad4 FIN exome

AF:

0.833

Gnomad4 NFE exome

AF:

0.841

Gnomad4 OTH exome

AF:

0.874

GnomAD4 genome

AF:

0.856

AC:

130358

AN:

152302

Hom.:

56012

Cov.:

AF XY:

0.858

AC XY:

63925

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.837

Gnomad4 AMR

AF:

0.912

Gnomad4 ASJ

AF:

0.924

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.953

Gnomad4 FIN

AF:

0.829

Gnomad4 NFE

AF:

0.839

Gnomad4 OTH

AF:

0.889

Alfa

AF:

0.854

Hom.:

36887

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Craniofacial-deafness-hand syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Waardenburg syndrome type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Waardenburg syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Waardenburg syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.4

DANN

Benign

0.61

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

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