2-222298550-AC-A

Variant names:

• chr2-222298550-AC-A
• NM_181458.4:c.65delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181458.4(PAX3):​c.65delG​(p.Arg22LeufsTer88) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX3 NM_181458.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.39

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]

CCDC140 (HGNC:26514): (CCDC140 long non-coding RNA) This gene encodes a protein that appears to be restricted to select higher primate species. This protein contains a C-terminal coiled-coil domain, which is a versatile structural motif consisting of multiple amphipathic alpha-helices that twist around each other to form a supercoil. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 231 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-222298550-AC-A is Pathogenic according to our data. Variant chr2-222298550-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 3601587.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.65delG	p.Arg22LeufsTer88	frameshift_variant	Exon 1 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.65delG	p.Arg22LeufsTer88	frameshift_variant	Exon 1 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Waardenburg syndrome type 1 Pathogenic:1

Jan 09, 2025

Institute of Rare Diseases, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1;PP1;PP4;PM2_Supporting -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-223163269;