rs141545923

chr2-222221307-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_181458.4(PAX3):c.873C>T(p.Pro291=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,020 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: PAX3 NM_181458.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.58

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]

LOC107985991 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-222221307-G-A is Benign according to our data. Variant chr2-222221307-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-222221307-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00167 (254/152294) while in subpopulation NFE AF= 0.00266 (181/68016). AF 95% confidence interval is 0.00234. There are 2 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.873C>T	p.Pro291=	synonymous_variant	6/9	ENST00000392070.7
LOC107985991	XR_001739903.2	n.618G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.873C>T	p.Pro291=	synonymous_variant	6/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00158 AC: 398 AN: 251208 Hom.: 2 AF XY: 0.00166 AC XY: 225 AN XY: 135744

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00214 AC: 3123 AN: 1461726 Hom.: 6 Cov.: 31 AF XY: 0.00213 AC XY: 1546 AN XY: 727174

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000824

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74472

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00171

EpiCase AF: 0.00245

EpiControl AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PAX3: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Pro290Pro in exon 6 of PAX3: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.3% (25/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs141545923). -

PAX3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Craniofacial-deafness-hand syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Waardenburg syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.47
Cadd	Benign	8.4
Dann	Benign	0.79

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

Other links and lift over

dbSNP: rs141545923; hg19: chr2-223086026; COSMIC: COSV60592203;