2-222201298-A-ACC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_181458.4(PAX3):c.*109_*110insGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,446,462 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 29)
  • Exomes 𝑓: 0.0045 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 2-222201298-A-ACC is Benign according to our data. Variant chr2-222201298-A-ACC is described in ClinVar as [Likely_benign]. Clinvar id is 1186210.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0045 (6506/1446462) while in subpopulation AFR AF= 0.0368 (1186/32272). AF 95% confidence interval is 0.035. There are 8 homozygotes in gnomad4_exome. There are 3121 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.*109_*110insGG		3_prime_UTR_variant	9/9	ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.*109_*110insGG		3_prime_UTR_variant	9/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2123 AN: 147936 Hom.: 20 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00716

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00409

Gnomad FIN AF: 0.0000992

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00336

Gnomad OTH AF: 0.00937

GnomAD4 exome AF: 0.00450 AC: 6506 AN: 1446462 Hom.: 8 Cov.: 34 AF XY: 0.00434 AC XY: 3121 AN XY: 719734

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0250

Gnomad4 SAS exome AF: 0.00377

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.00330

Gnomad4 OTH exome AF: 0.00491

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0143 AC: 2124 AN: 148034 Hom.: 20 Cov.: 29 AF XY: 0.0135 AC XY: 974 AN XY: 72030

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.00715

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0181

Gnomad4 SAS AF: 0.00389

Gnomad4 FIN AF: 0.0000992

Gnomad4 NFE AF: 0.00336

Gnomad4 OTH AF: 0.00927

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3832105; hg19: chr2-223066017;