rs387906947

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_181458.4(PAX3):​c.238C>T​(p.His80Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H80D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

PAX3
NM_181458.4 missense

Scores

16
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a DNA_binding_region Paired (size 127) in uniprot entity PAX3_HUMAN there are 53 pathogenic changes around while only 0 benign (100%) in NM_181458.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-222297061-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant 2-222297061-G-A is Pathogenic according to our data. Variant chr2-222297061-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2136213.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAX3NM_181458.4 linkc.238C>T p.His80Tyr missense_variant Exon 2 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.238C>T p.His80Tyr missense_variant Exon 2 of 9 1 NM_181458.4 ENSP00000375922.3 P23760-7

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Waardenburg syndrome type 1 Pathogenic:1
Jan 12, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM5_STR,PS2_MOD,PM1,PM2_SUP,PP3 -

not provided Uncertain:1
Jul 18, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;.;.;.;.;D;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.9
H;H;H;H;H;H;H;H
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.9
D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D
Polyphen
1.0, 0.99, 1.0
.;.;D;D;.;D;D;D
Vest4
0.83
MutPred
0.81
Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);Gain of methylation at K85 (P = 0.0739);
MVP
0.97
MPC
2.7
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.98
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: chr2-223161780; API