rs1553572976

chr2-222221306-C-CG

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.873_874insC(p.Gly292ArgfsTer118) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P291P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX3 NM_181458.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.58

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 2-222221306-C-CG is Pathogenic according to our data. Variant chr2-222221306-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 517263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.873_874insC	p.Gly292ArgfsTer118	frameshift_variant	6/9	ENST00000392070.7
LOC107985991	XR_001739903.2	n.620dup		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.873_874insC	p.Gly292ArgfsTer118	frameshift_variant	6/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 20, 2022

ACMG categories: PVS1,PM2,PP3,PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 04, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PAX3 protein in which other variant(s) (p.Gln405Argfs*29) have been determined to be pathogenic (PMID: 9654197; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 517263). This premature translational stop signal has been observed in individual(s) with Waardenburg syndrome, type 3 (PMID: 20127975). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly292Argfs*118) in the PAX3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 188 amino acid(s) of the PAX3 protein. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 31, 2017

The p.Gly291fs variant in PAX3 has been reported in 1 individual with Waardenbur g syndrome type I (Pingault 2010). It has not been identified in large populati on studies. This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 291 and leads to a premature t ermination codon 118 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Heterozygous loss of function of the PA X3 gene is an established disease mechanism in Waardenburg syndrome. In summary, this variant meets criteria to be classified as pathogenic for Waardenburg synd rome in an autosomal dominant manner based upon its predicted impact to the prot ein, presence in a previously reported affected individual, and extremely low fr equency 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: rs1553572976; hg19: chr2-223086025;