GeneBe

rs773327091

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_181458.4(PAX3):​c.124G>T​(p.Gly42Cys) 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. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 35)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PAX3
NM_181458.4 missense

Scores

17
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.86

Publications

5 publications found
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]
PAX3 Gene-Disease associations (from GenCC):
  • craniofacial-deafness-hand syndrome
    Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • Waardenburg syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • Waardenburg syndrome type 1
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
  • Waardenburg syndrome type 3
    Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr2-222297175-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 1.618 (below the threshold of 3.09). Trascript score misZ: 1.7934 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 3, Waardenburg syndrome type 1, Waardenburg syndrome, craniofacial-deafness-hand syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAX3NM_181458.4 linkc.124G>T p.Gly42Cys 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.124G>T p.Gly42Cys missense_variant Exon 2 of 9 1 NM_181458.4 ENSP00000375922.3 P23760-7

Frequencies

GnomAD3 genomes
Cov.:
35
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1445078
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
717486
African (AFR)
AF:
0.00
AC:
0
AN:
33050
American (AMR)
AF:
0.00
AC:
0
AN:
41986
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25782
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38620
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83848
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52104
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5732
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1104226
Other (OTH)
AF:
0.00
AC:
0
AN:
59730
GnomAD4 genome
Cov.:
35
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
.;.;.;.;.;D;.;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.0
H;H;H;H;H;H;H;H
PhyloP100
7.9
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-7.3
D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;.;D;D;D
Vest4
0.89
MutPred
0.93
Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);Loss of disorder (P = 0.0563);
MVP
1.0
MPC
2.7
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.97
gMVP
0.99
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs773327091; hg19: chr2-223161894; API