2-222298600-C-G

Variant names:

• chr2-222298600-C-G
• rs1414840887
• NM_181458.4:c.16G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181458.4(PAX3):​c.16G>C​(p.Gly6Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.16G>C	p.Gly6Arg	missense_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.16G>C	p.Gly6Arg	missense_variant	Exon 1 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454506 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 722902

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: 0.0000192

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 6 of the PAX3 protein (p.Gly6Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	.;.;.;.;.;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.0	L;L;L;L;L;L;L;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;T;T
Polyphen		1.0	.;.;D;D;.;D;D;D
Vest4		0.58
MutPred		0.47		Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);
MVP		0.85
MPC		2.9
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.95

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: rs1414840887; hg19: chr2-223163319;