chr2-222221300-AC-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181458.4(PAX3):​c.879delG​(p.Phe294SerfsTer87) 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 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G293G) has been classified as Likely benign. 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, single submitter P:1
• Conservation: PhyloP100: -2.08
• Publications: 0 publications found

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]

PAX3 Gene-Disease associations (from GenCC):

• craniofacial-deafness-hand syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Waardenburg syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

LOC107985991 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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-AC-A is Pathogenic according to our data. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222221300-AC-A is described in CliVar as Pathogenic. Clinvar id is 1447634.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.879delG	p.Phe294SerfsTer87	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.879delG	p.Phe294SerfsTer87	frameshift_variant	Exon 6 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251200 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 07, 2023

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: 20127975). 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.Val339Thrfs*70) have been determined to be pathogenic (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: 1447634). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe294Serfs*87) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.1
Mutation Taster		=1/199	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1553572967; hg19: chr2-223086019; COSMIC: COSV60589590;