NM_181458.4:c.879dupG

Variant names:

• chr2-222221300-A-AC
• rs1553572967
• NM_181458.4:c.879dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_181458.4(PAX3):​c.879dupG​(p.Phe294ValfsTer116) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAX3 NM_181458.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -2.08

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]

LOC107985991 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-222221300-A-AC is Pathogenic according to our data. Variant chr2-222221300-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 505425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.879dupG	p.Phe294ValfsTer116	frameshift_variant	Exon 6 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.879dupG	p.Phe294ValfsTer116	frameshift_variant	Exon 6 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 1 Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with Waardenburg syndrome (PMID: 8533800, 8589691, 9017978; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 874ins(G). ClinVar contains an entry for this variant (Variation ID: 505425). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe294Valfs*116) in the PAX3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 186 amino acid(s) of the PAX3 protein. -

Waardenburg syndrome;C5680250:Rare genetic deafness Pathogenic:1

Nov 08, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Phe293fs variant in PAX3 has been reported in 4 individuals with Waardenbu rg syndrome type I (Baldwin 1995, Tassabehji 1995, Morell 1997), and segregated with disease in 3 affected relatives from 2 families (Baldwin 1995, Morell 1997) . It has not been identified in large population studies. This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 293 and leads to a premature termination codon 116 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Heterozygous loss of function of the PAX3 gene is an established disease mechanism in individuals with Waardenburg syndrome. In summary, this variant mee ts criteria to be classified as pathogenic for Waardenburg syndrome in an autoso mal dominant manner based upon its predicted impact to the protein, presence in multiple previously reported affected individuals, co-segregations, and extremel y low frequency in the general population. -

Computational scores

Source: dbNSFP v4.3

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: rs1553572967; hg19: chr2-223086019;