2-222201518-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_181458.4(PAX3):c.1421-76C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,563,452 control chromosomes in the GnomAD database, including 7,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.071 (616 hom., cov: 31)
  • Exomes 𝑓: 0.086 (6837 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.48

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-222201518-G-A is Benign according to our data. Variant chr2-222201518-G-A is described in ClinVar as [Benign]. Clinvar id is 1246737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.1421-76C>T		intron_variant		ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.1421-76C>T		intron_variant		1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.0706 AC: 10740 AN: 152066 Hom.: 614 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.0700

GnomAD4 exome AF: 0.0861 AC: 121497 AN: 1411268 Hom.: 6837 Cov.: 24 AF XY: 0.0870 AC XY: 61367 AN XY: 705654

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.0345

Gnomad4 EAS exome AF: 0.0132

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.0805

Gnomad4 OTH exome AF: 0.0746

GnomAD4 genome AF: 0.0706 AC: 10739 AN: 152184 Hom.: 616 Cov.: 31 AF XY: 0.0732 AC XY: 5448 AN XY: 74382

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0820

Gnomad4 OTH AF: 0.0693

Alfa AF: 0.0808 Hom.: 93

Bravo AF: 0.0767

Asia WGS AF: 0.0590 AC: 203 AN: 3476

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	-0.26
Cadd	Benign	20
Dann	Benign	0.92

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: rs13014735; hg19: chr2-223066237;