2-222259374-A-G

Position:

• chr2-222259374-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181458.4(PAX3):​c.587-27091T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,190 control chromosomes in the GnomAD database, including 3,575 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3575 hom., cov: 32)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20

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=-0.51).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX3	NM_181458.4	c.587-27091T>C		intron_variant		ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.587-27091T>C		intron_variant		1	NM_181458.4	ENSP00000375922	A1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30252 AN: 152072 Hom.: 3564 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.201

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.199 AC: 30272 AN: 152190 Hom.: 3575 Cov.: 32 AF XY: 0.206 AC XY: 15340 AN XY: 74394

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.333

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.200

Alfa AF: 0.207 Hom.: 7197

Bravo AF: 0.204

Asia WGS AF: 0.351 AC: 1218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.67

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: rs4674639; hg19: chr2-223124093;