2-222298699-T-C

Variant names:

• chr2-222298699-T-C
• NM_181458.4:c.-84A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_181458.4(PAX3):​c.-84A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX3 NM_181458.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.527

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-222298699-T-C is Pathogenic according to our data. Variant chr2-222298699-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3601596.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.-84A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	ENST00000392070.7	NP_852123.1
PAX3	NM_181458.4	c.-84A>G		5_prime_UTR_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.-84A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	1	NM_181458.4	ENSP00000375922.3
PAX3	ENST00000392070.7	c.-84A>G		5_prime_UTR_variant	Exon 1 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely 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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.81

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: chr2-223163418;