2-222201151-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_181458.4(PAX3):c.*257G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,611,526 control chromosomes in the GnomAD database, including 31,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2231 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29638 hom.)
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.111

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-222201151-C-G is Benign according to our data. Variant chr2-222201151-C-G is described in ClinVar as [Benign]. Clinvar id is 1244902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222201151-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.*257G>C		3_prime_UTR_variant	9/9	ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.*257G>C		3_prime_UTR_variant	9/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22822 AN: 151908 Hom.: 2230 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.191 AC: 47808 AN: 250408 Hom.: 4975 AF XY: 0.198 AC XY: 26746 AN XY: 135354

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.273

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.198 AC: 288564 AN: 1459500 Hom.: 29638 Cov.: 32 AF XY: 0.200 AC XY: 145400 AN XY: 726182

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.150 AC: 22818 AN: 152026 Hom.: 2231 Cov.: 32 AF XY: 0.150 AC XY: 11181 AN XY: 74300

Gnomad4 AFR AF: 0.0398

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.157

Alfa AF: 0.129 Hom.: 343

Bravo AF: 0.143

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	9.3
Dann	Benign	0.55

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: rs3731858; hg19: chr2-223065870; COSMIC: COSV60588606; COSMIC: COSV60588606;