2-222298562-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_181458.4(PAX3):​c.54G>C​(p.Gln18His) variant causes a missense 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PAX3
NM_181458.4 missense

Scores

6
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.541
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37467277).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAX3NM_181458.4 linkc.54G>C p.Gln18His missense_variant Exon 1 of 9 ENST00000392070.7 NP_852123.1 P23760-7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAX3ENST00000392070.7 linkc.54G>C p.Gln18His missense_variant Exon 1 of 9 1 NM_181458.4 ENSP00000375922.3 P23760-7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.54G>C (p.Q18H) alteration is located in exon 1 (coding exon 1) of the PAX3 gene. This alteration results from a G to C substitution at nucleotide position 54, causing the glutamine (Q) at amino acid position 18 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.44
.;.;.;.;.;T;.;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.082
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Benign
0.37
T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
0.97
L;L;L;L;L;L;L;L
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-2.0
N;N;N;N;N;N;N;N
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D;D;D;D
Polyphen
0.83, 0.55, 0.89, 0.97, 0.68
.;.;P;P;.;P;D;P
Vest4
0.25
MutPred
0.15
Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);Gain of catalytic residue at N19 (P = 0.0553);
MVP
0.96
MPC
2.1
ClinPred
0.93
D
GERP RS
1.8
Varity_R
0.42
gMVP
0.93

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: chr2-223163281; API