2-222297170-A-G

Position:

• chr2-222297170-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.24

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]

ACMG classification

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	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	c.129T>C	p.Gly43=	synonymous_variant	2/9	1	NM_181458.4	ENSP00000375922	A1

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130250 AN: 152184 Hom.: 55961 Cov.: 36

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

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.: 61 AF XY: 0.860 AC XY: 618686 AN XY: 719310

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.: 36 AF XY: 0.858 AC XY: 63925 AN XY: 74466

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

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

Other links and lift over

dbSNP: rs12623857; hg19: chr2-223161889;